(1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists

ABSTRACT

Angiotensin-II antagonists of the formula ##STR1## wherein R 1  is, other than hydrogen and, inter alia, halogen, lower alkyl or cycloalkyl; R 2  is, inter alia, optionally substituted benzimidazol-2-yl, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl, butanesultam-1-yl, imidazol-4-yl, and tetrahydobenzimidazol-2-yl; R 3  is, inter alia, lower alkyl; and, R 4  is an acidic group, such as carboxyl or tetrazolyl. An exemplary compound is: 4&#39;-[(2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylic acid.

RELATED APPLICATIONS

This application is a division of Ser. No. 08/385,936, filed on Feb. 9,1995, now allowed, which is a continuation-in-part of the following fourprior applications:

(A) Ser. No. 08/201,139, filed on Feb. 24, 1994, which is a continuationof Ser. No. 07/832,193, filed on Feb. 6, 1992, both now abandoned;

(B) Ser. No. 08/257,608, filed on Jun. 9, 1994, which is a continuationof Ser. No. 08/007,315, filed on Jan. 21, 1993, both now abandoned;

(C) Ser. No. 08/237,477, filed on May 3, 1994, which is a continuationof Ser. No. 08/040,778, filed on Mar. 31, 1993, both now abandoned; and

(D) Ser. No. 08/094,835, filed on Jul. 20, 1993, now abandoned.

FIELD OF THE INVENTION

The invention relates to certain novel benzimidazoles and their use asmedicaments.

BACKGROUND AND BRIEF DESCRIPTION OF THE INVENTION

EP-A-0 392 317 has already described benzimidazoles which are valuableangiotensin antagonists.

It has now been found that the new benzimidazoles of formula I describedbelow are even more useful as angiotensin antagonists, particularlyangiotensin-II antagonists.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the invention comprises compounds of the formula I##STR2## wherein R₁, R₂, R₃ and R₄ are defined as set forth in optionsA, B, C or D, as follows:

Option A

R₁ in the 4-position represents a fluorine, chlorine or bromine atom, aC₁₋₄ -alkyl, a cycloalkyl, fluoromethyl, difluoromethyl ortrifluoromethyl group and

R₂ represents a C₃₋₅ -alkoxy group substituted in the 3-, 4- or5-position by an imidazolyl group, or R₂ may represent a C₂₋₅ -alkoxygroup substituted in the 2-, 3-, 4- or 5-position by a benzimidazolyl ortetrahydrobenzimidazolyl group, or, if R₄ represents a 1H-tetrazolylgroup, R₂ may also represent a 2-(imidazol-1-yl)-ethoxy group,

a C₁₋₄ -alkylsulphonyloxy group, a benzenesulphonyloxy orphenylalkanesulphonyloxy group,

an acylamino group optionally substituted at the nitrogen atom by a C₁₋₆-alkyl group or by a phenyl, cycloalkyl, phenylalkyl, cycloalkylalkyl,bicyclohexyl or biphenyl group, in which the acyl group is a C₁₋₇-alkanoyl group, a C₂₋₄ (alkoxycarbonyl) group, a C₁₋₆ -alkylsulphonylgroup, a benzoyl, benzenesulphonyl, phenylalkanesulphonyl,naphthalenesulphonyl, cycloalkylcarbonyl, phenylalkanoyl orcycloalkylalkanoyl group, in which the above-mentioned phenyl nuclei mayeach be mono- or disubstituted by a fluorine, chlorine or bromine atomor by a methyl or methoxy group and the substituents may be identical ordifferent,

a phthalimino, homophthalimino, 2-carboxyphenylcarbonyl-amino or2-carboxyphenylmethylamino group, in which a carbonyl group in aphthalimino group may be replaced by a methylene, alkylmethylene ordialkyl-methylene group, and a methylene group in a homophthaliminogroup may be substituted by one or two alkyl groups, and additionallythe above-mentioned phenyl nuclei may be mono- or disubstituted by alkylor alkoxy groups, whilst the substituents may be identical or different,and at the same time may be totally or partially hydrogenated,

a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group optionallysubstituted by one or two alkyl groups or by a tetramethylene orpentamethylene group, in which a methylene group may be replaced by acarbonyl or sulphonyl group,

a bicycloalkane-2,3-dicarboxylic acid imino orbicycloalkene-2,3-dicarboxylic acid imino group, wherein thebicycloalkane and bicycloalkene moieties may each contain 9 or 10 carbonatoms, may be substituted by 1, 2 or 3 methyl groups and may have anendomethylene group replaced by an oxygen atom,

an amidino group optionally substituted by one or two C₁₋₆ alkyl groups,

a glutaric acid imino group wherein the n-propylene group may beperfluorinated, or may be substituted by one or two alkyl groups or by atetramethylene or pentamethylene group,

a maleic acid imido group optionally mono- or di-substituted by an alkylor phenyl group, whilst the substituents may be identical or different,

a 5-membered heteroaromatic ring bound via a carbon atom or via an iminogroup and containing an imino group, an oxygen or sulphur atom, or animino group and an oxygen, sulphur or nitrogen atom, or R₂ may representa 6-membered heteroaromatic ring bound via a carbon atom and containing1 or 2 nitrogen atoms, whilst the abovementioned heteroaromatic ringsmay be substituted in the carbon structure by a C₁₋₆ alkyl or by aphenylalkyl group, and an n-propylene, n-butylene or 1,3-butadienylgroup may be linked to both the 5-membered and 6-membered heteroaromaticrings via two adjacent carbon atoms or an n-butylene or 1,3-butadienylgroup is linked thereto via an imino group and an adjacent carbon atomand, in an anellated pyridine ring thus formed, a methine group may bereplaced by a nitrogen atom and a vinylene group in the 3-, 4-positionrelative to the nitrogen atom of the pyridine ring formed may bereplaced by a sulphur atom or in an anellated phenyl ring thus formed,one or two methine groups may be replaced by N-atoms, whilstadditionally the above-mentioned fused aromatic or heteroaromatic ringsmay be monosubstituted in the carbon structure by a fluorine, chlorineor bromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino,alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl,difluoromethyl, trifluoromethyl, alkanoyl, aminosulphonyl,alkylaminosulphonyl or dialkylaminosulphonyl group or may bedisubstituted by fluorine or chlorine atoms or by methyl, methoxy orhydroxy groups, and two methyl substituents in the 1,2-position relativeto each other may be linked by a methylene or ethylene bridge and an--NH-- group optionally present in an imidazole ring may be substitutedby a C₁₋₆ -alkyl group, by a phenylalkyl group or by a cycloalkyl group,or

a pyrrolidine, piperidine or pyridine ring bound via a carbon atom, inwhich a phenyl group may be condensed onto the pyridine ring via twoadjacent carbon atoms and a methylene group adjacent to the N-atom in apyrrolidine or piperidine ring may be replaced by a carbonyl group,

an imidazolidinedione group optionally substituted by an alkyl,phenylalkyl, tetramethylene, pentamethylene or hexamethylene group,

a pyridazin-3-one or dihydro-pyridazin-3-one group which may besubstituted in the 2-position by an optionally phenyl substituted alkylgroup and additionally, in the carbon skeleton, by 1 or 2 alkyl groups,

an R₇ --NR₆ --CO--NR₅ -- group wherein

R₅ represents a hydrogen atom, a C₁₋₈ -alkyl group, a C₅₋₇ cycloalkylgroup or a phenylalkyl group,

R₆ represents a hydrogen atom, a C₁₋₈ -alkyl group, a C₃₋₅ -alkenylgroup, a phenyl group, a phenylalkyl group or a C₅₋₇ -cycloalkyl group,

R₇ represents a hydrogen atom or a C₁₋₆ -alkyl group or

one of the groups R₅, R₆ or R₇ may also represent a bicyclohexyl orbiphenylyl group or

R₆ and R₇ together with the nitrogen atom between them represent anunbranched C₄₋₆ -alkyleneimino group or a morpholino group or

R₅ and R₆ together represent a C₂₋₄ -alkylene group,

or, R₂ may represent a 1H,3H-quinazolin-2,4-dion-3-yl orpentamethylene-oxazolin-2-yl group or

R₁ represents, in the 5-, 6- or 7-position, a fluorine, chlorine orbromine atom, a C₁₋₄ -alkyl group, a fluoromethyl, difluoromethyl ortrifluoromethyl group and

R₂ represents a 5-membered heteroaromatic ring bound via a carbon atomor via an imino group and containing an imino group, an oxygen orsulphur atom or, an imino group and an oxygen, sulphur or nitrogen atom,or R₂ represents a 6-membered heteroaromatic ring bound via a carbonatom and containing 1 or 2 nitrogen atoms, whilst the abovementionedheteroaromatic rings may be substituted in the carbon skeleton by a C₁₋₆alkyl or by a phenylalkyl group and an n-propylene, n-butylene or1,3-butadienyl group may be linked via two adjacent carbon atoms to boththe 5-membered and 6-membered heteroaromatic rings or an n-butylene or1,3-butadienyl group may be linked to said 5-membered and 6-memberedheteroaromatic rings via an imino group and an adjacent carbon atom and,in an anellated pyridine ring thus formed, a methine group may bereplaced by a nitrogen atom and a vinylene group in the 3-, 4-positionrelative to the nitrogen atom of the pyridine ring formed may bereplaced by a sulphur atom or in an anellated phenyl ring thus formed,one or two methine groups may be replaced by N-atoms, whilstadditionally the abovementioned fused aromatic or heteroaromatic ringsmay be monosubstituted on the carbon skeleton by a fluorine, chlorine orbromine atom or by an alkyl, alkoxy, hydroxy, phenyl, nitro, amino,alkylamino, dialkylamino, alkanoylamino, cyano, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, fluoromethyl,difluoromethyl, trifluoromethyl, alkanoyl, aminosulphonyl,alkylaminosulphonyl or dialkylaminosulphonyl group or may bedisubstituted by fluorine or chlorine atoms or by methyl, methoxy orhydroxy groups, and two methyl substituents in the 1,2-position relativeto each other may be linked by a methylene or ethylene bridge and an--NH-- group optionally present in an imidazole ring may be substitutedby a C₁₋₆ -alkyl group, by a phenylalkyl group or by a cycloalkyl group,

or, R₂ may represent a pyrrolidine, piperidine or pyridine ring boundvia a carbon atom, in which a phenyl group may be condensed onto thepyridine ring via 2 adjacent carbon atoms and a methylene group adjacentto the N-atom in a pyrrolidine or piperidine ring may be replaced by acarbonyl group,

R₃ represents a hydrogen atom or a C₁₋₅ -alkyl group in which amethylene group may be replaced by an oxygen or sulphur atom, or R₃ mayrepresent a C₃₋₅ cycloalkyl group, and

R₄ represents a carboxy, cyano, 1H-tetrazolyl or1-triphenylmethyltetrazolyl group, a C₂₋₅ (alkoxycarbonyl) group, analkanesulphonylaminocarbonyl, arylsulphonylamino-carbonyl ortrifluoromethanesulphonylaminocarbonyl group,

whilst, unless otherwise specified, an alkanoyl, alkyl or alkoxy moietymentioned hereinbefore may contain in each case 1 to 3 carbon atoms anda cycloalkyl moiety mentioned hereinbefore may contain 3 to 7 carbonatoms in each case,

Option B

R₁ is in the 4-position and represents a C₁₋₃ -alkyl group, a fluorine,chlorine or bromine atom,

R₂ represents an oxazol-4-yl or thiazol-4-yl group optionallysubstituted in the 2-position by a C₁₋₆ -alkyl group or by a phenylgroup, or an imidazol-4-yl group optionally substituted in the2-position by a C₁₋₆ -alkyl group or by a phenyl group, whilst theimidazol-4-yl group is substituted in the 1-position

by a C₁₋₇ -alkyl group which may be substituted in the 1-, 2-, 3-, 4-,5-, 6- or 7-position by a carboxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl or 1-oxido-thiomorpholinocarbonyl group,

by a C₂₋₄ -alkyl group substituted in the 2-, 3- or 4-position by ahydroxy, alkoxy, alkoxyalkoxy, dialkylamino, pyrrolidino, piperidino,hexamethyleneimino, morpholino, thiomorpholino, 1-oxido-thiomorpholinoor imidazol-1-yl group,

by an alkyl group which is substituted by a trifluoromethyl group, by aC₃₋₇ -cycloalkyl group or by a phenyl group optionally mono- ordisubstituted by fluorine or chlorine atoms or by trifluoromethyl,methyl or methoxy groups,

by an alkyl group substituted by two phenyl groups

or by a C₃₋₇ -cycloalkyl group,

where unless otherwise specified the above-mentioned alkyl and alkoxymoieties may each contain 1 to 3 carbon atoms,

R₃ represents a C₂₋₄ -alkyl group, an alkoxy or alkylthio group having 2or 3 carbon atoms in the alkyl moiety, or a cyclopropyl or cyclobutylgroup and

R₄ represents a group which may be converted in vivo into a carboxygroup, or a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolylor 2-triphenylmethyl-tetrazolyl group,

Option C

R₁ denotes a fluorine, chlorine or bromine atom or a fluoromethyl,difluoromethyl, trifluoromethyl or alkyl group,

R₂ denotes an imidazol-2-yl group optionally substituted in the1-position by the group R_(a), wherein

R_(a) denotes a phenyl or phenylalkyl group, in which the phenyl nucleusmay be mono- or disubstituted by alkyl, hydroxy or alkoxy groups and thesubstituents may be identical or different, a C₃₋₇ -cycloalkyl group ora C₁₋₆ -alkyl group in which the alkyl moiety may additionally besubstituted by a group which can be metabolised into a carboxy group invivo, by a trifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylaminocarbonyl group or from position 2 by ahydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino,piperidino or morpholino group,

a 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group,

an imidazolium-2-yl group which is substituted in the 1- and 3-positionsby groups R_(b), which groups may be identical or different, whilst

R_(b) denotes a phenylalkyl group in which the phenyl nucleus may bemono- or disubstituted by alkyl, hydroxy or alkoxy groups and thesubstituents may be identical or different, or a C₁₋₆ -alkyl group inwhich the alkyl moiety may additionally be substituted by a group whichcan be metabolised into a carboxy group in vivo, or by atrifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylamino- carbonyl group,

an oxazol-2-yl or thiazol-2-yl group, whilst in the above mentionedimidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moieties,the 4-, 5-positions may be substituted by a C₁₋₅ -alkyl group or by aphenyl group, wherein the substituents may be identical or different, oran n-propylene or n-butylene bridge may be added via the 4-,5-positions,

an oxazolin-2-yl or imidazolin-2-yl group substituted in the 4-positionby R₉ and R₁₀ and in the 5-position by R₈, whereby an imino group mayadditionally be substituted by R_(a), or an R₈ CO--(R₉ CR₁₀)--NR_(a)--CO-- group, wherein

R_(a) is defined as hereinbefore,

R₈ to R₁₀, which may be identical or different, denote hydrogen atoms,C₁₋₅ -alkyl groups or phenyl groups,

R₃ denotes a C₁₋₅ -alkyl group, a C₃₋₅ -cycloalkyl group, an alkoxy oralkylthio group each having 1 to 4 carbon atoms and

R₄ denotes a group which can be metabolised into a carboxy group invivo, a carboxy, cyano, 2,5-dihydro-5-oxo-1.2.4-oxadiazol-3-yl,1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or2-triphenylmethyl-tetrazolyl group,

whilst unless otherwise specified all the above-mentioned alkyl andalkoxy groups may each contain 1 to 3 carbon atoms,

Option D

R₁ denotes a fluorine, chlorine or bromine atom, a C₁₋₃ -alkyl group, aC₃₋₇ -cycloalkyl group, a fluoromethyl, difluoromethyl ortrifluoromethyl group,

R₂ denotes a phthalimino or homophthalimino group, whilst a carbonylgroup in a phthalimino group may be replaced by a methylene group and amethylene group in a homophthalimino group may be substituted by one ortwo C₁₋₃ -alkyl groups,

5-, 6- or 7-membered alkyleneimino group (optionally substituted by oneor two C₁₋₃ -alkyl groups) in which a methylene group is replaced by acarbonyl or sulphonyl group, a maleic acid imido group optionally mono-or disubstituted by a C₁₋₃ -alkyl group or by a phenyl group, whilst thesubstituents may be identical or different,

a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl groupoptionally substituted in the 1-position by a C₁₋₆ -alkyl group or by aC₃₋₅ -cycloalkyl group (whilst the phenyl nucleus of one of theabove-mentioned benzimidazole groups may additionally be substituted bya fluorine atom or a methyl or trifluoromethyl group), animidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl,imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl,imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, apyrrolidine, piperidine or pyridine ring bound via a carbon atom, whilsta phenyl group may be condensed on to the pyridine ring via two adjacentcarbon atoms and a methylene group adjacent to the N-atom in apyrrolidine or piperidine ring may be replaced by a carbonyl group, or

an R₇ --NR₆ --CO--NR₅ -- group wherein

R₅ denotes a hydrogen atom, a C₁₋₅ -alkyl group, a cyclohexyl or benzylgroup,

R₆ denotes a hydrogen atom, a C₁₋₆ -alkyl group, an allyl, cyclohexyl,benzyl or phenyl group,

R₇ denotes a hydrogen atom or a C₁₋₃ -alkyl group or

R₆ and R₇ together with the nitrogen atom between them denote anunbranched cyclic C₄₋₆ -alkyleneimino group or a morpholino group or

R₅ and R₆ together denote a C₂₋₃ -alkylene group,

R₃ denotes a C₁₋₅ -alkyl group, a C₃₋₅ -cycloalkyl group or a C₁₋₃-alkoxy group and

R₄ denotes a tetrazolyl group substituted in the 1- or 2-position by anR_(a) --CO--O--CH₂ -- group, or an R_(b) --CO--O--(R_(c) CH)--O--CO--,R_(a) O--CO-- or R_(b) O--CO--O--(R_(c) CH)--O--CO-- group, wherein

R_(a) denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, methoxymethyl or cinnamyl group,

R_(b) denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or3-phenylpropyl group and

R_(c) denotes a hydrogen atom or a methyl group,

or if

(i) R₁ and R₂ are as hereinbefore defined and R₃ denotes an alkoxygroup, R₄ may denote a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group or,if

(ii) R₁ is as hereinbefore defined, R₂ has the meanings givenhereinbefore with the exception of the 1-methyl-benzimidazol-2-yl groupand R₃ denotes a cyclopropyl group, R₄ may represent a carboxy group or,if

(iii) R₁ and R₃ are as hereinbefore defined and R₂ denotes abutanesultam-1-yl group, R₄ may denote a carboxy group or, if

(iv) R₁ is as hereinbefore defined, R₂ denotes a1-methyl-5-fluoro-benzimidazol-2-yl group and R₃ denotes an ethyl group,R₄ may represent a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group.

Unless otherwise specified, as used in Options B and C, the term "agroup which may be converted in vivo into a carboxy group" denotes, forexample, the esters thereof of formulae

    --CO--OR',

    --CO--O--(HCR")--O--CO--R'" and

    --CO--O--(HCR")--O--CO-OR'"

wherein

R' denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, methoxymethyl or cinnamyl group,

R" denotes a hydrogen atom or a methyl group and

R'" denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or3-phenylpropyl group.

The invention also comprises pharmaceutically acceptable acid additionsalts of the above-described compounds of formula I, and the 1,3-isomermixtures.

As examples of the definitions of the groups R₁ to R₄ mentionedhereinbefore:

In Compounds According to Option A

R₁ may represent a fluorine, chlorine or bromine atom, a methyl, ethyl,n-propyl, isopropyl, isobutyl, n-butyl, 1-methyl-n-propyl,2-methyl-n-propyl, tert.butyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, fluoromethyl, difluoromethyl or trifluoromethylgroup,

R₂ may represent a 3-(imidazol-1-yl)propoxy, 4-(imidazol-1-yl)butoxy,5-(imidazol-1-yl)pentoxy, 2-(benzimidazol-1-yl)ethoxy,3-(benzimidazol-1-yl)-propoxy, 4-(benzimidazol-1-yl)butoxy,5-(benzimidazol-1-yl)-pentoxy, 2-(tetrahydrobenzimidazol-1-yl)ethoxy,3-(tetrahydrobenzimidazol-1-yl)propoxy,4-(tetrahydrobenzimidazol-1-yl)butoxy,5-(tetrahydrobenzimidazol-1-yl)pentoxy, methanesulphonyloxy,ethanesulphonyloxy, n-propanesulphonyloxy, isopropanesulphonyloxy,n-butanesulphonyloxy, benzenesulphonyloxy, 4-fluorobenzenesulphonyloxy,4-bromobenzenesulphonyloxy, 4-methylbenzenesulphonyloxy,4-methoxybenzene-sulphonyloxy, 3,4-dichlorobenzenesulphonyloxy,phenyl-methanesulphonyloxy, 2-phenylethanesulphonyloxy,3-phenylpropanesulphonyloxy, formylamino, acetylamino, propionylamino,butanoylamino, isobutanoylamino, pentanoylamino, 3-methyl-butanoylamino,hexanoylamino, methoxycarbonylamino, ethoxycarbonylamino,n-propoxycarbonylamino, isopropoxycarbonylamino, methanesulphonylamino,ethanesulphonylamino, n-propanesulphonylamino, isopropanesulphonylamino,n-butanesulphonylamino, n-pentanesulphonylamino, n-hexanesulphonylamino,benzamido, benzenesulphonylamido, 4-fluorobenzenesulphonamido,4-chlorobenzenesulphonamido, 4-bromobenzenesulphonamido,4-methylbenzenesulphonamido, 4-methoxybenzenesulphonamido,phenylmethanesulphonyl-amido, 2-phenylethanesulphonylamido,3-phenylpropane-sulphonylamido, naphthalen-1-yl-sulphonamido,naphthalen-2-yl-sulphonylamido, cyclopentylcarbonyl-amido,cyclohexylcarbonylamido, cycloheptylcarbonyl-amido, phenylacetylamido,3-phenylpropionylamido, cyclopentylacetylamido,3-cyclopentylpropionylamido, cyclohexylacetylamido,3-cyclohexylpropionylamido, cycloheptylacetylamido,3-cycloheptylpropionylamido, N-methyl-formylamino, N-methylacetylamino,N-methyl-propionylamino, N-methyl-butanoylamino,N-methyl-isobutanoylamino, N-methyl-pentanoylamino,N-methyl-3-methyl-butanoylamino, N-methyl-hexanoylamino,N-methyl-methoxycarbonylamino, N-methyl-ethoxycarbonylamino,N-methyl-n-propoxycarbonylamino, N-methyl-isopropoxy-carbonylamino,N-methyl-methanesulphonylamino, N-methyl-ethanesulphonylamino,N-methyl-n-propanesulphonylamino, N-methyl-isopropanesulphonylamino,N-methyl-n-butane-sulphonylamino, N-methyl-n-pentanesulphonylamino,N-methyl-n-hexanesulphonylamino, N-methyl-benzamido,N-methyl-benzenesulphonylamido, N-methyl-4-fluorobenzene-sulphonamido,N-methyl-4-chlorobenzenesulphonamido,N-methyl-4-bromobenzenesulphonamido,N-methyl-4-methylbenzenesulphonamido,N-methyl-4-methoxybenzenesulphonamido,N-methyl-phenylmethanesulphonylamido,N-methyl-2-phenylethanesulphonylamido,N-methyl-3-phenylpropanesulphonylamido,N-methyl-naphthalen-1-ylsulphonamido,N-methyl-naphthalen-2-yl-sulphonylamido,N-methyl-cyclopentylcarbonylamido, N-methyl-cyclohexylcarbonylamido,N-methyl-cycloheptylcarbonylamido, N-methyl-phenylacetylamido,N-methyl-3-phenylpropionyl-amido, N-methyl-cyclopentylacetylamido,N-methyl-3-cyclopentylpropionylamido, N-methyl-cyclohexylacetyl-amido,N-methyl-3-cyclohexylpropionylamido, N-methyl-cycloheptylacetylamido,N-methyl-3-cycloheptylpropionyl-amido, N-ethyl-formylamino,N-ethyl-acetylamino, N-ethyl-propionylamino, N-ethyl-butanoylamino,N-ethyl-isobutanoylamino, N-ethyl-pentanoylamino,N-ethyl-3-methyl-butanoylamino, N-ethyl-hexanoylamino,N-ethyl-methoxycarbonylamino, N-ethyl-ethoxycarbonylamino,N-ethyl-n-propoxycarbonylamino, N-ethyl-isopropoxy-carbonylamino,N-ethyl-methanesulphonylamino, N-ethyl-ethanesulphonylamino,N-ethyl-n-propanesulphonylamino, N-ethyl-isopropanesulphonylamino,N-ethyl-n-butanesulphonylamino, N-ethyl-n-pentanesulphonylamino,N-ethyl-n-hexanesulphonylamino, N-ethyl-benzamido,N-ethylbenzenesulphonylamido, N-ethyl-4-fluorobenzene-sulphonamido,N-ethyl-4-chlorobenzenesulphonamido, N-ethyl-4-bromobenzenesulphonamido,N-ethyl-4-methylbenzenesulphonamido,N-ethyl-4-methoxybenzenesulphonamido,N-ethyl-phenylmethanesulphonylamido,N-ethyl-2-phenylethanesulphonylamido,N-ethyl-3-phenylpropanesulphonylamido,N-ethyl-naphthalen-1-yl-sulphonamido,N-ethyl-naphthalen-2-yl-sulphonylamido,N-ethyl-cyclopentylcarbonylamido, N-ethyl-cyclohexylcarbonyl-amido,N-ethyl-cycloheptylcarbonylamido, N-ethyl-phenylacetylamido,N-ethyl-3-phenyl-propionylamido, N-ethyl-cyclopentylacetylamido,N-ethyl-3-cyclopentyl-propionylamido, N-ethyl-cyclohexylacetylamido,N-ethyl-3-cyclohexylpropionylamido, N-ethyl-cycloheptylacetyl-amido,N-ethyl-3-cycloheptylpropionylamido, N-n-propyl-formylamino,N-n-propyl-acetylamino, N-n-propyl-propionylamino,N-n-propyl-butanoylamino, N-n-propyl-isobutanoylamino,N-n-propyl-pentanoylamino, N-n-propyl-(3-methyl-butanoyl)amino,N-n-propyl-hexanoylamino, N-isopropyl-formylamino,N-isopropyl-acetylamino, N-isopropyl-propionylamino,N-isopropyl-butanoylamino, N-isopropyl-isobutanoylamino,N-isopropyl-pentanoylamino, N-isopropyl-(3-methyl-butanoyl)amino,N-isopropyl-hexanoylamino, N-n-butyl-formylamino, N-n-butyl-acetylamino,N-n-butyl-propionylamino, N-n-butyl-butanoylamino,N-n-butyl-isobutanoylamino, N-n-butyl-pentanoylamino,N-n-butyl-(3-methyl-butanoyl)amino, N-n-butyl-hexanoylamino,N-isobutyl-formylamino, N-isobutyl-acetylamino,N-isobutyl-propionylamino, N-isobutyl-butanoylamino,N-isobutyl-isobutanoylamino, N-isobutyl-pentanoylamino,N-n-pentyl-formylamino, N-n-pentyl-acetylamino,N-n-pentyl-propionylamino, N-n-pentyl-butanoylamino,N-n-pentyl-isobutanoylamino, N-n-pentyl-pentanoylamino,N-(1-methyl-butyl)-formylamino, N-(1-methyl-butyl)-acetylamino,N-(1-methyl-butyl)-propionylamino, N-(1-methyl-butyl)-butanoylamino,N-(1-methyl-butyl)-isobutanoylamino, N-(1-methyl-butyl)-pentanoylamino,N-(2-methyl-butyl)-formylamino, N-(2-methyl-butyl)-acetylamino,N-(2-methyl-butyl)-propionylamino, N-(2-methyl-butyl)-butanoylamino,N-(2-methyl-butyl)-isobutanoylamino, N-(2-methyl-butyl)-pentanoylamino,N-(3-methyl-butyl)-formylamino, N-(3-methyl-butyl)-acetylamino,N-(3-methyl-butyl)-propionylamino, N-(3-methyl-butyl)-butanoylamino,N-(3-methyl-butyl)-isobutanoylamino, N-(3-methyl-butyl)-pentanoylamino,N-n-hexyl-formylamino, N-n-hexyl-acetylamino, N-n-hexyl-propionylamino,N-n-hexyl-butanoylamino, N-n-hexyl-isobutanoylamino,N-n-hexyl-pentanoylamino, N-n-propyl-cyclohexylcarbonylamino,N-n-propyl-cyclohexylacetylamino,N-n-propyl-3-(cyclohexyl)propionylamino,N-isopropyl-cyclohexylcarbonylamino, N-isopropyl-cyclohexylacetylamino,N-isopropyl-3-(cyclohexyl)-propionylamino,N-n-butyl-cyclohexylcarbonylamino, N-n-butyl-cyclohexylacetylamino,N-n-butyl-3-(cyclohexyl)-propionylamino,N-isobutyl-cyclohexylcarbonylamino, N-isobutyl-cyclohexylacetylamino,N-isobutyl-3-(cyclohexyl)propionylamino,N-n-pentyl-cyclohexylcarbonylamino, N-n-pentyl-cyclohexylacetylamino,N-n-pentyl-3-(cyclohexyl)propionylamino,N-n-hexyl-cyclohexylcarbonylamino, N-n-hexyl-cyclohexylacetyl-amino,N-n-hexyl-3-(cyclohexyl)propionylamino, phthalimino,5-methoxy-phthalimino, 5,6-dimethoxy-phthalimino, 6-methoxy-phthalimino,homophthalimino, 4,4-dimethyl-homophthalimino,7-methoxy-homophthalimino, 6,7-dimethoxy-homophthalimino,7-methoxy-4,4-dimethyl-homophthalimino,6,7-dimethoxy-4,4-dimethyl-homophthalimino,1,2,3,6-tetrahydrophthalimino, hexahydrophthalimino,cis-hexahydrophthalimino, trans-hexahydrophthalimino,1-oxo-isoindolin-2-yl, 3,4-dimethylphthalimino,4,5-dimethyl-1,2,3,6-tetrahydrophthalimino,4,5-dimethyl-hexahydrophthalimino, 4,5-dimethyl-1-oxo-isoindolin-2-yl,3,4-dimethoxy-phthalimino, 4,5-dimethoxy-1,2,3,6-tetrahydrophthalimino,4,5-dimethoxy-hexahydrophthalimino, 4,5-dimethoxy-1-oxo-isoindolin-2-yl,2-carboxyphenylmethylamino, 2-carboxyphenylmethylenecarbonylamino,pyrrolidino, 2-methylpyrrolidino, 3-ethylpyrrolidino,3-isopropylpyrrolidino, piperidino, 3-methylpiperidino,4-methylpiperidino, 4-ethylpiperidino, 4-isopropylpiperidino,hexamethyleneimino, 3-methylhexamethyleneimino,4-methylhexamethyleneimino, 3-ethylhexamethyleneimino,4-isopropylhexamethyleneimino, 3,3-dimethyl-pyrrolidino,3,4-dimethyl-pyrrolidino, 3,3-dimethyl-piperidino,3,4-dimethyl-piperidino, 4,4-dimethyl-piperidino,3,3-dimethyl-hexamethyleneimino, 3,4-dimethyl-hexamethyleneimino,4,4-dimethyl-hexamethyleneimino, 3,5-dimethyl-hexamethyleneimino,3,3-tetramethylene-pyrrolidino, 3,3-pentamethylene-pyrrolidino,3,3-tetramethylene-piperidino, 3,3-pentamethylene-piperidino,4,4-tetramethylene-piperidino, 4,4-pentamethylene-piperidino,3,3-tetramethylene-hexamethyleneimino,3,3-pentamethylene-hexamethyleneimino,4,4-tetramethylene-hexamethylene-imino,4,4-pentamethylene-hexamethyleneimino, 2-oxo-pyrrolidino,2-oxo-piperidino, 2-oxo-hexamethyleneimino, propanesultam-1-yl,butanesultam-1-yl, pentanesultam-1-yl,endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic acid imino,methyl-5-norbornene-2,3-dicarboxylic acid imino,3,6-endoxo-1,2,3,6-tetrahydrophthalimino,5-norbornen-endo-2,3-dicarboxylic acid imino, glutarimino,3,3-tetramethylene-glutarimino, 3,3-pentamethylene-glutarimino,2,2-dimethyl-glutarimino, 3-methyl-glutarimino,3,3-dimethyl-glutarimino, 3-ethyl-glutarimino,3-ethyl-3-methyl-glutarimino, 1,3-cyclopentanedicarbonylimino,2,4-dimethyl-glutarimino, 2,4-di-n-propyl-glutarimino, glutaramino,3,3-tetramethylene-glutaramino, 3,3-pentamethylene-glutaramino,2,2-dimethyl-glutaramino, 3-methyl-glutaramino,3,3-dimethyl-glutaramino, 3-ethyl-glutaramino,3-ethyl-3-methyl-glutaramino, 1,3-cyclopentanedicarbonylamino,2,4-dimethyl-glutaramino, 2,4-di-n-propyl-glutaramino, maleic acidamido, maleic acid imido, 2-methyl-maleic acid amido, 3-methyl-maleicacid amido, 2-methyl-maleic acid imido, 2-phenyl-maleic acid amido,3-phenyl-maleic acid amido, 2-phenyl-maleic acid imido,2,3-dimethyl-maleic acid amido, 3-methyl-2-phenyl-maleic acid amido,2-methyl-3-phenyl-maleic acid amido, 2-methyl-3-phenyl-maleic acidimido, 2,3-diphenyl-maleic acid amido, 2,3-diphenyl-maleic acid amido,pyrrolidin-2-yl, pyrrolidin-2-on-5-yl, piperidin-2-yl,piperidin-2-on-1-yl, piperidin-2-on-6-yl, quinolin-2-yl,isoquinolin-1-yl, isoquinolin-3-yl, pyridin-2-yl, 4-methylimidazol-2-yl,1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 1-n-hexylimidazol-4-yl,1-n-hexylimidazol-5-yl, 1-benzylimidazol-4-yl, 1-benzylimidazol-5-yl,1,2-dimethylimidazol-4-yl, 1,2-dimethylimidazol-5-yl,1-n-pentyl-2-methyl-imidazol-4-yl, 1-n-pentyl-2-methyl-imidazol-5-yl,1-n-butyl-2-methyl-imidazol-4-yl, 1-n-butyl-2-methyl-imidazol-5-yl,1-benzyl-2-methyl-imidazol-4-yl, 1-benzyl-2-methyl-imidazol-5-yl,benzimidazol-2-yl, 1-methylbenzimidazol-2-yl, 1-ethylbenzimidazol-2-yl,1-n-propylbenzimidazol-2-yl, 1-isopropylbenzimidazol-2-yl,1-n-butylbenzimidazol-2-yl, 1-isobutylbenzimidazol-2-yl,1-n-pentylbenzimidazol-2-yl, 1-n-hexylbenzimidazol-2-yl,1-cyclopropyl-benzimidazol-2-yl, 1-cyclobutylbenzimidazol-2-yl,1-cyclopentylbenzimidazol-2-yl, 1-cyclohexylbenzimidazol-2-yl,5-nitro-benzimidazol-2-yl, 5-amino-benzimidazol-2-yl,5-acetamido-benzimidazol-2-yl, 5-methyl-benzimidazol-2-yl,5-methoxy-benzimidazol-2-yl, 5-ethoxy-benzimidazol-2-yl,1-methyl-5-methoxy-benzimidazol-2-yl, 1,5-dimethyl-benzimidazol-2-yl,1,6-dimethyl-benzimidazol-2-yl, 1,4-dimethyl-benzimidazol-2-yl,5,6-dimethyl-benzimidazol-2-yl, 1,5,6-trimethyl-benzimidazol-2-yl,5-chloro-benzimidazol-2-yl, 5-chloro-1-methyl-benzimidazol-2-yl,6-chloro-1-methyl-benzimidazol-2-yl,5,6-dichloro-1-methyl-benzimidazol-2-yl ,5-dimethylamino-benzimidazol-2-yl,5-dimethylamino-1-ethyl-benzimidazol-2-yl,5,6-dimethoxy-1-methyl-benzimidazol-2-yl,5,6-dimethoxy-1-ethyl-benzimidazol-2-yl,5-fluoro-1-methyl-benzimidazol-2-yl,6-fluoro-1-methyl-benzimidazol-2-yl,5-trifluoromethyl-benzimidazol-2-yl,5-trifluoromethyl-1-methyl-benzimidazol-2-yl,4-cyano-1-methyl-benzimidazol-2-yl,5-carboxy-1-methyl-benzimidazol-2-yl, 5-aminocarbonyl-benzimidazol-2-yl,5-aminocarbonyl-1-methyl-benzimidazol-2-yl,5-dimethylaminosulphonyl-1-methyl-benzimidazol-2-yl,5-methoxycarbonyl-1-methyl-benzimidazol-2-yl,5-methylaminocarbonyl-1-methyl-benzimidazol-2-yl,5-dimethylaminocarbonyl-1-methyl-benzimidazol-2-yl,4,6-difluoro-1-methyl-benzimidazol-2-yl,5-acetyl-1-methyl-benzimidazol-2-yl,5,6-dihydroxy-1-methyl-benzimidazol-2-yl, imidazo[1,2-a]pyridin-2-yl,5-methyl-imidazo[1,2-a]pyridin-2-yl,6-methyl-imidazo[1,2-a]-pyridin-2-yl,7-methylimidazo[1,2-a]-pyridin-2-yl,8-methyl-imidazo[1,2-a]pyridin-2-yl,5,7-dimethyl-imidazo[1,2-a]pyridin-2-yl,6-aminocarbonyl-imidazo[1,2-a]pyridin-2-yl,6-chloro-imidazo[1,2-a]-pyridin-2-yl,6-bromo-imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, 5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-yl,imidazo[4,5-b]pyridin-2-yl, 1-methyl-imidazo[4,5-b]pyridin-2-yl,1-n-hexyl-imidazo[4,5-b]pyridin-2-yl,1-cyclopropyl-imidazo[4,5-b]pyridin-2-yl,1-cyclohexyl-imidazo[4,5-b]pyridin-2-yl,4-methyl-imidazo[4,5-b]pyridin-2-yl,6-methyl-imidazo[4,5-b]pyridin-2-yl,1,4-dimethyl-imidazo[4,5-b]pyridin-2-yl,1,6-dimethyl-imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl,1-methylimidazo[4,5-c]pyridin-2-yl,1-n-hexyl-imidazo[4,5-c]-pyridin-2-yl,1-cyclopropyl-imidazo[4,5-c]pyridin-2-yl,1-cyclohexyl-imidazo[4,5-c]pyridin-2-yl, imidazo[2,1-b]-thiazol-6-yl,3-methyl-imidazo[2,1-b]thiazol-6-yl,2-phenyl-imidazo[2,1-b]thiazol-6-yl,3-phenyl-imidazo[2,1-b]thiazol-6-yl,2,3-dimethyl-imidazo[2,1-b]-thiazol-6-yl,2,3-trimethylene-imidazo[2,1-b]thiazol-6-yl,2,3-tetramethylene-imidazo[2,1-b]thiazol-6-yl,imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl,imidazo[1,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl,imidazo[4,5-b]pyrazin-2-yl, imidazo [4,5-c]pyridazin-2-yl,imidazo[4,5-d]pyridazin-2-yl, imidazolidin-2,4-dion-3-yl,5-methyl-imidazolidin-2,4-dion-3-yl, 5-ethyl-imidazolidin-2,4-dion-3-yl,5-n-propyl-imidazolidin-2,4-dion-3-yl,5-benzyl-imidazolidin-2,4-dion-3-yl,5-(2-phenylethyl)-imidazolidin-2,4-dion-3-yl,5-(3-phenylpropyl)-imidazolidin-2,4-dion-3-yl,5,5-tetramethylene-imidazolidin-2,4-dion-3-yl,5,5-pentamethylene-imidazolidin-2,4-dion-3-yl,5,5-hexamethylene-imidazolidin-2,4-dion-3-yl,1-methyl-imidazolidin-2,4-dion-3-yl, 1-benzyl-imidazolin-2,4-dion-3-yl,4,5-dihydro-2H-pyridazin-3-on-6-yl,2-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2-ethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2-n-propyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2-isopropyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2-benzyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2-(2-phenylethyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl,2-(3-phenylpropyl)-4,5-dihydro-2H-pyridazin-3-on-6-yl,4-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,5-methyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,5,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,4,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2,4-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2,5-dimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2,4,5-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2,4,4-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2,5,5-trimethyl-4,5-dihydro-2H-pyridazin-3-on-6-yl,2H-pyridazin-3-on-6-yl, 2-methyl-pyridazin-3-on-6-yl,2-ethyl-pyridazin-3-on-6-yl, 2-n-propyl-pyridazin-3-on-6-yl,2-isopropyl-pyridazin-3-on-6-yl, 2-benzyl-pyridazin-3-on-6-yl,2-(2-phenylethyl)-pyridazin-3-on-6-yl,2-(3-phenylpropyl)-pyridazin-3-on-6-yl, 4-methyl-pyridazin-3-on-6-yl,5-methyl-pyridazin-3-on-6-yl, 4,5-dimethyl-pyridazin-3-on-6-yl,2,4-dimethyl-pyridazin-3-on-6-yl, 2,5-dimethyl-pyridazin-3-on-6-yl,2,4,5-trimethyl-pyridazin-3-on-6-yl, aminocarbonylamino,methylaminocarbonylamino, dimethylaminocarbonylamino,N-methylaminocarbonyl-methylamino,N-(dimethylaminocarbonyl)-methylamino,N-dimethylaminocarbonyl-ethylamino,N-dimethylamino-carbonyl-isopropylamino,N-(dimethylaminocarbonyl)-n-pentylamino,N-methylaminocarbonyl-ethylamino, N-methylaminocarbonyl-n-pentylamino,N-methylamino-carbonyl-n-hexylamino, N-methylaminocarbonyl-n-octylamino,N-methylaminocarbonyl-cyclohexylamino, ethylaminocarbonylamino,N-ethylaminocarbonyl-methylamino, N-ethylaminocarbonyl-ethylamino,N-ethylaminocarbonyl-n-hexylamino, N-ethylaminocarbonyl-n-heptylamino,N-ethylaminocarbonyl-cyclohexylamino, diethylaminocarbonylamino,N-(diethylaminocarbonyl)-methylamino,N-(diethylaminocarbonyl)-ethylamino,N-(diethylaminocarbonyl)-n-butylamino,N-(diethylamino-carbonyl)-n-hexylamino,N-(diethylaminocarbonyl)-n-octylamino, isopropylaminocarbonylamino,N-isopropyl-aminocarbonylmethylamino, n-butylaminocarbonylamino,N-(n-butylaminocarbonyl)-methylamino,N-(n-butylamino-carbonyl)-ethylamino,N-(n-butylaminocarbonyl)-isopropylamino,N-(n-butylaminocarbonyl)-n-butylamino,N-(n-butylaminocarbonyl)-n-hexylamino,N-(n-butylamino-carbonyl)-cyclohexylamino,N-(di-(n-butyl)-aminocarbonyl)-amino,N-(di-(n-butyl)-aminocarbonyl)-methylamino,N-(di-(n-butyl)-aminocarbonyl)-ethylamino,N-(di-(n-butyl)-aminocarbonyl)-n-butylamino,N-(di-(n-butyl)-aminocarbonyl)-n-hexylamino,N-(n-pentylamino-carbonyl)-methylamino,N-(n-pentylaminocarbonyl)-ethylamino,N-(n-hexylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino,n-heptylaminocarbonylamino, n-octylaminocarbonylamino,N-(n-hexylaminocarbonyl)-n-butylamino,N-(n-hexylaminocarbonyl)-n-pentylamino,N-(n-hexylaminocarbonyl)-n-hexylamino,N-(n-hexylamino-carbonyl)-cyclohexylamino,di-(n-hexyl)-aminocarbonyl-amino,N-(di-(n-hexyl)-aminocarbonyl)-methylamino,N-((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylamino-carbonylamino,N-cyclohexylaminocarbonyl-methylamino,N-cyclohexylaminocarbonyl-ethylamino,N-cyclohexylaminocarbonyl-n-butylamino,N-cyclohexylaminocarbonyl-isobutylamino,N-cyclohexylaminocarbonyl-n-pentylamino,N-cyclohexylaminocarbonyl-n-hexylamino,N-cyclohexylaminocarbonyl-cyclohexylamino,N-(ethyl-cyclohexylaminocarbonyl)-methylamino,N-(propyl-cyclohexylaminocarbonyl)-methylamino,N-(n-butyl-cyclohexylaminocarbonyl)-methylamino,allylaminocarbonylamino, benzylaminocarbonylamino,N-benzylaminocarbonyl-isobutylamino, phenylaminocarbonyl-amino,pyrrolidinocarbonylamino, pyrrolidinocarbonyl-methylamino,piperidinocarbonylamino, hexamethylene-iminocarbonylamine,morpholinocarbonylamino, 3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-methyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-ethyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-isopropyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-butyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-isobutyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-pentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-hexyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-cyclopentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-cyclohexyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-cycloheptyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-benzyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-n-propyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-isopropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-(2-phenylethyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl or3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl group, and

R₃ may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert.butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl,3-methyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, methylmercapto, ethylmercapto,n-propylmercapto, isopropylmercapto or n-butylmercapto group.

In Compounds According to Option B

R₁ may represent a fluorine or chlorine atom, a methyl, ethyl, n-propylor isopropyl group,

R₂ may represent an oxazol-4-yl, 2-methyl-oxazol-4-yl,2-ethyl-oxazol-4-yl, 2-n-propyl-oxazol-4-yl, 2-isopropyl-oxazol-4-yl,2-n-butyl-oxazol-4-yl, 2-isobutyl-oxazol-4-yl, 2-n-pentyl-oxazol-4-yl,2-isoamyl-oxazol-4-yl, 2-n-hexyl-oxazol-4-yl, 2-phenyl-oxazol-4-yl,thiazol-4-yl, 2-methyl-thiazol-4-yl, 2-ethyl-thiazol-4-yl,2-n-propyl-thiazol-4-yl, 2-isopropyl-thiazol-4-yl,2-n-butyl-thiazol-4-yl, 2-isobutyl-thiazol-4-yl,2-n-pentyl-thiazol-4-yl, 2-isoamyl-thiazol-4-yl, 2-n-hexyl-thiazol-4-yl,2-phenyl-thiazol-4-yl, 1-methyl-imidazol-4-yl, 1-ethyl-imidazol-4-yl,1-n-propyl-imidazol-4-yl, 1-isopropyl-imidazol-4-yl,1-n-butyl-imidazol-4-yl, 1-isobutyl-imidazol-4-yl,1-n-pentyl-imidazol-4-yl-, 1-isoamyl-imidazol-4-yl,1-n-hexyl-imidazol-4-yl, 1-n-hexyl-2-methyl-imidazol-4-yl,1-(1-methyl-n-pentyl)-imidazol-4-yl, 1-(1-ethyl-n-butyl)-imidazol-4-yl,1-(1-methyl-n-hexyl)-imidazol-4-yl, 1-(1-ethyl-n-pentyl)-imidazol-4-yl,1-(1-n-propyl-n-butyl)-imidazol-4-yl, 1-n-heptyl-imidazol-4-yl,1-ethyl-2-methyl-imidazol-4-yl, 1-n-propyl-2-methyl-imidazol-4-yl,1-isopropyl-2-methyl-imidazol-4-yl, 1-n-butyl-2-methyl-imidazol-4-yl,1-isobutyl-2-methyl-imidazol-4-yl, 1-n-pentyl-2-methyl-imidazol-4-yl,1-isoamyl-2-methyl-imidazol-4-yl, 1-n-hexyl-2-methyl-imidazol-4-yl,1-n-heptyl-2-methyl-imidazol-4-yl, 1-cyclopropylmethyl-imidazol-4-yl,1-cyclobutylmethyl-imidazol-4-yl, 1-cyclopentylmethyl-imidazol-4-yl,1-cyclohexylmethyl-imidazol-4-yl, 1-cycloheptylmethyl-imidazol-4-yl,1-(2-cyclo-propylethyl)-imidazol-4-yl,1-(2-cyclobutylethyl)-imidazol-4-yl,1-(2-cyclopentylethyl)-imidazol-4-yl,1-(2-cyclohexylethyl)-imidazol-4-yl,1-(2-cycloheptyl-ethyl)-imidazol-4-yl,1-(3-cyclopropylpropyl)-imidazol-4-yl-,1-(3-cyclobutylpropyl)-imidazol-4-yl,1-(3-cyclopentylpropyl)-imidazol-4-yl,1-(3-cyclohexyl-propyl)-imidazol-4-yl,1-(3-cycloheptylpropyl)-imidazol-4-yl,1-(2,2,2-trifluoroethyl)-imidazol-4-yl,1-(3,3,3-trifluoropropyl)-imidazol-4-yl, 1-benzyl-imidazol-4-yl,1-(2-phenylethyl)-imidazol-4-yl, 1-(3-phenylpropyl)-imidazol-4-yl,1-(4-fluorobenzyl)-imidazol-4-yl, 1-(4-chlorobenzyl)-imidazol-4-yl,1-(3-chlorobenzyl)-imidazol-4-yl,1-(4-trifluoromethyl-benzyl)-imidazol-4-yl,1-(3-methyl-benzyl)-imidazol-4-yl, 1-(4-methyl-benzyl)-imidazol-4-yl,1-(3-methoxy-benzyl)-imidazol-4-yl, 1-(4-methoxy-benzyl)-imidazol-4-yl,1-(3,4-dimethoxy-benzyl)-imidazol-4-yl,1-(3,5-dimethoxy-benzyl)-imidazol-4-yl,1-cyclopropylmethyl-2-methyl-imidazol-4-yl,1-cyclobutylmethyl-2-methyl-imidazol-4-yl,1-cyclopentylmethyl-2-methyl-imidazol-4-yl,1-cyclohexylmethyl-2-methyl-imidazol-4-yl,1-cyclo-heptylmethyl-2-methyl-imidazol-4-yl,1-(2-cyclopropylethyl)-2-methyl-imidazol-4-yl,1-(2-cyclobutylethyl)-2-methyl-imidazol-4-yl,1-(2-cyclopentylethyl)-2-methyl-imidazol-4-yl,1-(2-cyclohexylethyl)-2-methyl-imidazol-4-yl,1-(2-cycloheptylethyl)-2-methyl-imidazol-4-yl,1-(3-cyclopropylpropyl)-2-methyl-imidazol-4-yl,1-(3-cyclobutylpropyl)-2-methyl-imidazol-4-yl,1-(3-cyclopentylpropyl)-2-methyl-imidazol-4-yl,1-(3-cyclohexylpropyl)-2-methyl-imidazol-4-yl,1-(3-cycloheptylpropyl)-2-methyl-imidazol-4-yl,1-(2,2,2-trifluoroethyl)-2-methyl-imidazol-4-yl-,1-(3,3,3-trifluoropropyl)-2-methyl-imidazol-4-yl-,1-benzyl-2-methyl-imidazol-4-yl,1-(2-phenylethyl)-2-methyl-imidazol-4-yl,1-(3-phenylpropyl)-2-methyl-imidazol-4-yl,1-(4-fluorobenzyl)-2-methyl-imidazol-4-yl,1-(4-chlorobenzyl)-2-methyl-imidazol-4-yl,1-(3-chloro-benzyl)-2-methyl-imidazol-4-yl,1-(4-trifluoromethyl-benzyl)-2-methyl-imidazol-4-yl,1-(3-methyl-benzyl)-2-methyl-imidazol-4-yl,1-(4-methyl-benzyl)-2-methyl-imidazol-4-yl,1-(3-methoxy-benzyl)-2-methyl-imidazol-4-yl,1-(4-methoxy-benzyl)-2-methyl-imidazol-4-yl,1-(3,4-dimethoxy-benzyl)-2-methyl-imidazol-4-yl,1-(3,5-dimethoxy-benzyl)-2-methyl-imidazol-4-yl,1-carboxymethyl-imidazol-4-yl, 1-(2-carboxyethyl)-imidazol-4-yl,1-(3-carboxypropyl)-imidazol-4-yl, 1-(4-carboxybutyl)-imidazol-4-yl,1-(5-carboxypentyl)-imidazol-4-yl, 1-(6-carboxyhexyl)-imidazol-4-yl,1-(7-carboxyheptyl)-imidazol-4-yl,1-methoxycarbonylmethyl-imidazol-4-yl,1-(2-methoxycarbonylethyl)-imidazol-4-yl,1-(3-methoxycarbonylpropyl)-imidazol-4-yl,1-(4-methoxycarbonylbutyl)-imidazol-4-yl,1-(5-methoxycarbonylpentyl)-imidazol-4-yl,1-(6-methoxycarbonylhexyl)-imidazol-4-yl,1-(7-methoxycarbonylheptyl)-imidazol-4-yl,1-ethoxycarbonylmethyl-imidazol-4-yl,1-(2-ethoxycarbonylethyl)-imidazol-4-yl,1-(3-ethoxycarbonylpropyl)-imidazol-4-yl,1-(4-ethoxycarbonylbutyl)-imidazol-4-yl,1-(5-ethoxycarbonylpentyl)-imidazol-4-yl,1-(6-ethoxycarbonylhexyl)-imidazol-4-yl,1-(7-ethoxycarbonylheptyl)-imidazol-4-yl,1-n-propoxycarbonylmethyl-imidazol-4-yl,1-(2-n-propoxycarbonylethyl)-imidazol-4-yl,1-(3-n-propoxycarbonylpropyl)-imidazol-4-yl,1-(4-n-propoxycarbonylbutyl)-imidazol-4-yl,1-(5-n-propoxycarbonyl-pentyl)-imidazol-4-yl,1-(6-n-propoxycarbonylhexyl)-imidazol-4-yl,1-(7-n-propoxycarbonylheptyl)-imidazol-4-yl,1-isopropoxycarbonylmethyl-imidazol-4-yl,1-(2-isopropoxycarbonylethyl)-imidazol-4-yl,1-(3-isopropoxycarbonylpropyl)-imidazol-4-yl,1-(4-isopropoxycarbonylbutyl)-imidazol-4-yl,1-(5-isopropoxycarbonylpentyl)-imidazol-4-yl,1-(6-isopropoxycarbonylhexyl)-imidazol-4-yl,1-(7-isopropoxycarbonylheptyl)-imidazol-4-yl,1-aminocarbonylmethyl-imidazol-4-yl,1-(2-aminocarbonyl-ethyl)-imidazol-4-yl,1-(3-aminocarbonylpropyl)-imidazol-4-yl,1-(4-aminocarbonylbutyl)-imidazol-4-yl,1-(5-aminocarbonylpentyl)-imidazol-4-yl,1-(6-aminocarbonylhexyl)-imidazol-4-yl,1-(7-aminocarbonyl-heptyl)-imidazol-4-yl,1-methylaminocarbonylmethyl-imidazol-4-yl,1-(2-methylaminocarbonylethyl)-imidazol-4-yl,1-(3-methylaminocarbonylpropyl)-imidazol-4-yl,1-(4-methylaminocarbonylbutyl)-imidazol-4-yl,1-(5-methylaminocarbonylpentyl)-imidazol-4-yl,1-(6-methylaminocarbonylhexyl)-imidazol-4-yl,1-(7-methylaminocarbonylheptyl)-imidazol-4-yl,1-ethylaminocarbonylmethyl-imidazol-4-yl,1-(2-ethylaminocarbonylethyl)-imidazol-4-yl,1-(3-ethylaminocarbonyl-propyl)-imidazol-4-yl,1-(4-ethylaminocarbonylbutyl)-imidazol-4-yl,1-(5-ethylaminocarbonylpentyl)-imidazol-4-yl,1-(6-ethylaminocarbonylhexyl)-imidazol-4-yl,1-(7-ethylaminocarbonylheptyl)-imidazol-4-yl,1-n-propylaminocarbonylmethyl-imidazol-4-yl,1-(2-n-propylaminocarbonylethyl)-imidazol-4-yl,1-(3-n-propylaminocarbonylpropyl)-imidazol-4-yl,1-(4-n-propylaminocarbonylbutyl)-imidazol-4-yl,1-(5-n-propylaminocarbonylpentyl)-imidazol-4-yl,1-(6-n-propylaminocarbonylhexyl)-imidazol-4-yl,1-(7-n-propylaminocarbonylheptyl)-imidazol-4-yl,1-isopropylaminocarbonylmethyl-imidazol-4-yl,1-(2-isopropylaminocarbonylethyl)-imidazol-4-yl,1-(3-isopropylaminocarbonylpropyl)-imidazol-4-yl,1-(4-isopropylaminocarbonylbutyl)-imidazol-4-yl,1-(5-isopropylaminocarbonylpentyl)-imidazol-4-yl,1-(6-isopropylaminocarbonylhexyl)-imidazol-4-yl,1-(7-isopropylaminocarbonylheptyl)-imidazol-4-yl,1-dimethylaminocarbonylmethyl-imidazol-4-yl,1-(2-dimethylaminocarbonylethyl)-imidazol-4-yl,1-(3-dimethylaminocarbonylpropyl)-imidazol-4-yl,1-(4-dimethylaminocarbonylbutyl)-imidazol-4-yl,1-(5-dimethylaminocarbonylpentyl)-imidazol-4-yl,1-(6-dimethylaminocarbonylhexyl)-imidazol-4-yl,1-(7-dimethylaminocarbonylheptyl)-imidazol-4-yl,1-diethylaminocarbonylmethyl-imidazol-4-yl,1-(2-diethylaminocarbonylethyl)-imidazol-4-yl,1-(3-diethylaminocarbonylpropyl)-imidazol-4-yl,1-(4-diethylaminocarbonylbutyl)-imidazol-4-yl,1-(5-diethylaminocarbonylpentyl)-imidazol-4-yl,1-(6-diethylaminocarbonylhexyl)-imidazol-4-yl,1-(7-diethylaminocarbonylheptyl)-imidazol-4-yl,1-di-n-propylaminocarbonylmethyl-imidazol-4-yl,1-(2-di-n-propylaminocarbonylethyl)-imidazol-4-yl,1-(3-di-n-propylaminocarbonylpropyl)-imidazol-4-yl,1-(4-di-n-propylaminocarbonylbutyl)-imidazol-4-yl,1-(5-di-n-propylaminocarbonylpentyl)-imidazol-4-yl,1-(6-di-n-propylaminocarbonylhexyl)-imidazol-4-yl,1-(7-di-n-propylaminocarbonylheptyl)-imidazol-4-yl,1-diisopropylaminocarbonylmethyl-imidazol-4-yl,1-(2-diisopropylaminocarbonylethyl)-imidazol-4-yl,1-(3-diisopropylaminocarbonylpropyl)-imidazol-4-yl,1-(4-diisopropylaminocarbonylbutyl)-imidazol-4-yl,1-(5-diisopropylaminocarbonylpentyl)-imidazol-4-yl,1-(6-diisopropylaminocarbonylhexyl)-imidazol-4-yl,1-(7-diisopropylaminocarbonylheptyl)-imidazol-4-yl,1-morpholinocarbonylmethyl-imidazol-4-yl,1-(2-morpholinocarbonylethyl)-imidazol-4-yl,1-(3-morpholinocarbonylpropyl)-imidazol-4-yl,1-(4-morpholinocarbonylbutyl)-imidazol-4-yl,1-(5-morpholinocarbonylpentyl)-imidazol-4-yl,1-(6-morpholinocarbonylhexyl)-imidazol-4-yl,1-(7-morpholinocarbonylheptyl)-imidazol-4-yl,1-thiomorpholinocarbonylmethyl-imidazol-4-yl,1-(2-thiomorpholinocarbonylethyl)-imidazol-4-yl,1-(3-thiomorpholinocarbonylpropyl)-imidazol-4-yl,1-(4-thiomorpholinocarbonylbutyl)-imidazol-4-yl,1-(5-thiomorpholinocarbonylpentyl)-imidazol-4-yl,1-(6-thiomorpholinocarbonylhexyl)-imidazol-4-yl,1-(7-thiomorpholinocarbonylheptyl)-imidazol-4-yl,1-oxidothiomorpholinocarbonylmethyl-imidazol-4-yl,1-(2-oxidothiomorpholinocarbonylethyl)-imidazol-4-yl,1-(3-oxidothiomorpholinocarbonylpropyl)-imidazol-4-yl,1-(4-oxidothiomorpholinocarbonylbutyl)-imidazol-4-yl,1-(5-oxidothiomorpholinocarbonylpentyl)-imidazol-4-yl,1-(6-oxidothiomorpholinocarbonylhexyl)-imidazol-4-yl,1-(7-oxidothiomorpholinocarbonylheptyl)-imidazol-4-yl,1-carboxymethyl-2-methyl-imidazol-4-yl,1-(2-carboxyethyl)-2-methyl-imidazol-4-yl,1-(3-carboxypropyl)-2-methyl-imidazol-4-yl,1-(4-carboxybutyl)-2-methyl-imidazol-4-yl,1-(5-carboxypentyl)-2-methyl-imidazol-4-yl,1-(6-carboxyhexyl)-2-methyl-imidazol-4-yl,1-(7-carboxyheptyl)-2-methyl-imidazol-4-yl,1-methoxycarbonylmethyl-2-methyl-imidazol-4-yl-(2-methoxycarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-methoxycarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-methoxycarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-methoxycarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-methoxycarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-methoxycarbonylheptyl)-2-methyl-imidazol-4-yl,1-ethoxycarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-ethoxycarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-ethoxycarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-ethoxycarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-ethoxycarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-ethoxycarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-ethoxycarbonylheptyl)-2-methyl-imidazol-4-yl,1-n-propoxycarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-n-propoxycarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-n-propoxycarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-n-propoxycarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-n-propoxycarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-n-propoxycarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-n-propoxycarbonylheptyl)-2-methyl-imidazol-4-yl,1-isopropoxycarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-isopropoxycarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-isopropoxycarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-isopropoxycarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-isopropoxycarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-isopropoxycarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-isopropoxycarbonylheptyl)-2-methyl-imidazol-4-yl,1-aminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-aminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-aminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-aminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-aminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-aminocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-aminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-methylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-methylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-methylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-methylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-methylaminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-methylaminocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-methylaminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-ethylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-ethylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-ethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-ethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-ethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-ethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-ethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-n-propylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-n-propylaminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-n-propylaminocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-isopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-isopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-isopropylaminocarbonyl-propyl)-2-methyl-imidazol-4-yl,1-(4-isopropylamino-carbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-isopropylaminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-isopropylaminocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-isopropylaminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-dimethylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-dimethylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-dimethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-dimethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-dimethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-dimethylaminocarbonyl-hexyl)-2-methyl-imidazol-4-yl,1-(7-dimethylamino-carbonylheptyl)-2-methyl-imidazol-4-yl,1-diethylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-diethylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-diethylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-diethylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-diethylaminocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-diethylaminocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-diethylaminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-di-n-propylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-di-n-propylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-di-n-propylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-di-n-propylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-di-n-propylaminocarbonyl-pentyl)-2-methyl-imidazol-4-yl,1-(6-di-n-propylamino-carbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-di-n-propylaminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-diisopropylaminocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-diisopropylaminocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-diisopropylaminocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-diisopropylaminocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-diisopropylaminocarbonyl-pentyl)-2-methyl-imidazol-4-yl,1-(6-diisopropylamino-carbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-diisopropyl-aminocarbonylheptyl)-2-methyl-imidazol-4-yl,1-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-morpholinocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-morpholinocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-morpholinocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-morpholinocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-morpholinocarbonylheptyl)-2-methyl-imidazol-4-yl,1-thiomorpholinocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-thiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-thiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-thiomorpholinocarbonyl-butyl)-2-methyl-imidazol-4-yl,1-(5-thiomorpholinocarbonylpentyl)-2-methyl-imidazol-4-yl,1-(6-thiomorpholinocarbonyl-hexyl)-2-methyl-imidazol-4-yl,1-(7-thiomorpholino-carbonylheptyl)-2-methyl-imidazol-4-yl,1-oxidothio-morpholinocarbonylmethyl-2-methyl-imidazol-4-yl,1-(2-oxidothiomorpholinocarbonylethyl)-2-methyl-imidazol-4-yl,1-(3-oxidothiomorpholinocarbonylpropyl)-2-methyl-imidazol-4-yl,1-(4-oxidothiomorpholinocarbonylbutyl)-2-methyl-imidazol-4-yl,1-(5-oxidothiomorpholinocarbonyl-pentyl)-2-methyl-imidazol-4-yl,1-(6-oxidothio-morpholinocarbonylhexyl)-2-methyl-imidazol-4-yl,1-(7-oxidothiomorpholinocarbonylheptyl)-2-methyl-imidazol-4-yl,1-(2-hydroxyethyl)-imidazol-4-yl, 1-(3-hydroxypropyl)-imidazol-4-yl,1-(4-hydroxybutyl)-imidazol-4-yl, 1-(2-methoxyethyl)-imidazol-4-yl,1-(3-methoxypropyl)-imidazol-4-yl, 1-(4-methoxybutyl)-imidazol-4-yl,1-(2-ethoxyethyl)-imidazol-4-yl, 1-(3-ethoxypropyl)-imidazol-4-yl,1-(4-ethoxybutyl)-imidazol-4-yl, 1-(2-n-propoxyethyl)-imidazol-4-yl,1-(3-n-propoxypropyl)-imidazol-4-yl, 1-(4-n-propoxybutyl)-imidazol-4-yl,1-(2-isopropoxyethyl)-imidazol-4-yl,1-(3-isopropoxypropyl)-imidazol-4-yl,1-(4-isopropoxy-butyl)-imidazol-4-yl,1-(2-imidazol-1-yl-ethyl)-imidazol-4-yl,1-(3-imidazol-1-yl-propyl)-imidazol-4-yl,1-(4-imidazol-1-yl-butyl)-imidazol-4-yl,1-(2,2-diphenyl-ethyl)-imidazol-4-yl,1-(3,3-diphenyl-propyl)-imidazol-4-yl,1-(4,4-diphenyl-butyl)-imidazol-4-yl,1-(2-hydroxyethyl)-2-methyl-imidazol-4-yl,1-(3-hydroxy-propyl)-2-methyl-imidazol-4-yl,1-(4-hydroxybutyl)-2-methyl-imidazol-4-yl,1-(2-methoxyethyl)-2-methyl-imidazol-4-yl,1-(3-methoxypropyl)-2-methyl-imidazol-4-yl,1-(4-methoxybutyl)-2-methyl-imidazol-4-yl,1-(2-ethoxyethyl)-2-methyl-imidazol-4-yl,1-(3-ethoxypropyl)-2-methyl-imidazol-4-yl,1-(4-ethoxybutyl)-2-methyl-imidazol-4- yl,1-(2-n-propoxyethyl)-2-methyl-imidazol-4-yl,1-(3-n-propoxypropyl)-2-methyl-imidazol-4-yl,1-(4-n-propoxybutyl)-2-methyl-imidazol-4-yl,1-(2-isopropoxyethyl)-2-methyl-imidazol-4-yl,1-(3-isopropoxypropyl)-2-methyl-imidazol-4-yl,1-(4-isopropoxybutyl)-2-methyl-imidazol-4-yl,1-(2-imidazol-1-yl-ethyl)-2-methyl-imidazol-4-yl,1-(3-imidazol-1-yl-propyl)-2-methyl-imidazol-4-yl,1-(4-imidazol-1-yl-butyl)-2-methyl-imidazol-4-yl,1-(2,2-diphenyl-ethyl)-2-methyl-imidazol-4-yl,1-(3,3-diphenyl-propyl)-2-methyl-imidazol-4-yl,1-(4,4-diphenyl-butyl)-2-methyl-imidazol-4-yl,1-[2-(2-methoxyethoxy)-ethyl]-imidazol-4-yl,1-[3-(2-methoxyethoxy)propyl]-imidazol-4-yl,1-[4-(2-methoxyethoxy)-butyl]-imidazol-4-yl,1-[2-(2-ethoxyethoxy)-ethyl]-imidazol-4-yl,1-[3-(2-ethoxyethoxy)-propyl]-imidazol-4-yl,1-[4-(2-ethoxyethoxy)-butyl]-imidazol-4-yl,1-[2-(2-n-propoxyethoxy)-ethyl]-imidazol-4-yl,1-[3-(2-n-propoxyethoxy)-propyl]-imidazol-4-yl,1-[4-(2-n-propoxyethoxy)-butyl]-imidazol-4-yl,1-[2-(2-isopropoxyethoxy)-ethyl]-imidazol-4-yl,1-[3-(2-isopropoxyethoxy)-propyl]-imidazol-4-yl,1-[4-(2-isopropoxyethoxy)-butyl]-imidazol-4-yl,1-(2-dimethylaminoethyl)-imidazol-4-yl,1-(2-diethylamino-ethyl)-imidazol-4-yl,1-(2-di-n-propylamino-ethyl)-imidazol-4-yl,1-(2-diisopropylaminoethyl)-imidazol-4-yl,1-(3-dimethylaminopropyl)-imidazol-4-yl,1-(3-diethylaminopropyl)-imidazol-4-yl,1-(3-di-n-propylamino-propyl)-imidazol-4-yl,1-(3-di-isopropylamino-propyl)-imidazol-4-yl,1-(4-dimethylamino-butyl)-imidazol-4-yl,1-(4-diethylamino-butyl)-imidazol-4-yl,1-(4-di-n-propylamino-butyl)-imidazol-4-yl,1-(4-diisopropylamino-butyl)-imidazol-4-yl,1-(2-morpholino-ethyl)-imidazol-4-yl,1-(3-morpholino-propyl)-imidazol-4-yl,1-(4-morpholino-butyl)-imidazol-4-yl,1-(2-pyrrolidino-ethyl)-imidazol-4-yl,1-(3-pyrrolidino-propyl)-imidazol-4-yl,1-(4-pyrrolidino-butyl)-imidazol-4-yl,1-(2-piperidino-ethyl)-imidazol-4-yl,1-(3-piperidino-propyl)-imidazol-4-yl,1-(4-piperidino-butyl)-imidazol-4-yl,1-(2-hexamethyleneimino-ethyl)-imidazol-4-yl,1-(3-hexamethyleneimino-propyl)-imidazol-4-yl,1-(4-hexamethyleneimino-butyl)-imidazol-4-yl,1-(2-thiomorpholino-ethyl)-imidazol-4-yl,1-(3-thiomorpholino-propyl)-imidazol-4-yl,1-(4-thiomorpholino-butyl)-imidazol-4-yl,1-[2-(1-oxido-thiomorpholino)-ethyl]-imidazol-4-yl,1-[3-(1-oxido-thiomorpholino)-propyl]-imidazol-4-yl or1-[4-(1-oxido-thiomorpholino)-butyl]-imidazol-4-yl group,

R₃ may represent an ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert.butyl, cyclopropyl, cyclobutyl, ethoxy, n-propoxy, isopropoxy,ethylthio, n-propylthio or isopropylthio group and

R₄ may represent a hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl,n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl,isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl,isoamyloxycarbonyl, n-hexyloxy-carbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, benzyloxycarbonyl, 1-phenylethyloxycarbonyl,2-phenylethyloxycarbonyl, 3-phenylpropyloxycarbonyl,methoxymethoxycarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl,propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl,isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl,isopentanoyloxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl,n-hexanoyloxymethoxycarbonyl, cyclopentanoyloxy-methoxycarbonyl,cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl,2-phenylpropionyloxy-methoxycarbonyl,3-phenylpropionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl,benzoyloxy-methoxycarbonyl, 1-acetoxyethoxycarbonyl,1-propionyloxyethoxycarbonyl, 1-n-butyryloxy-ethoxycarbonyl,1-isobutyryloxyethoxycarbonyl, 1-n-pentanoyloxyethoxycarbonyl,1-isopentanoyloxy-ethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl,1-n-hexanoyloxyethoxycarbonyl, 1-cyclopentanoyl-oxyethoxycarbonyl,1cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl,1-(1-phenylpropionyloxy)-ethoxycarbonyl,1-(2-phenylpropionyloxy)-ethoxycarbonyl,1-(3-phenylbutyryloxy)ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl,methoxycarbonyloxymethoxy-carbonyl, ethoxycarbonyloxymethoxycarbonyl,n-propyloxycarbonyloxymethoxycarbonyl,isopropyloxycarbonyloxymethoxycarbonyl,n-butyloxycarbonyloxymethoxycarbonyl,isobutyloxycarbonyloxymethoxy-carbonyl,tert.butyloxycarbonyloxymethoxycarbonyl,n-pentyloxycarbonyloxymethoxycarbonyl,isoamyloxycarbonyloxymethoxycarbonyl,n-hexyloxycarbonyloxymethoxy-carbonyl,cyclopentyloxycarbonyloxymethoxycarbonyl,cyclohexyloxycarbonyloxymethoxycarbonyl,benzyloxycarbonyloxymethoxycarbonyl,1-phenylethoxycarbonyloxymethoxycarbonyl,2-phenylethoxycarbonyloxy-methoxycarbonyl,3-phenylpropyloxycarbonyloxy-methoxycarbonyl,cinnamyloxycarbonyloxymethoxycarbonyl,1-(methoxycarbonyloxy)ethoxycarbonyl,1-(ethoxycarbonyloxy)-ethoxycarbonyl,1-(n-propyloxycarbonyloxy)-ethoxycarbonyl,1-(isopropyloxycarbonyloxy)-ethoxycarbonyl,1-(n-butyloxycarbonyloxy)-ethoxycarbonyl,1-(isobutyloxycarbonyloxy)-ethoxycarbonyl,1-(tert.butyloxy-carbonyloxy)-ethoxycarbonyl,1-(n-pentyloxycarbonyloxy)-ethoxycarbonyl,1-(isoamyloxycarbonyloxy)-ethoxycarbonyl,1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl,1-(cyclopentyloxycarbonyloxy)-ethoxy-carbonyl,1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl,cyclopentylcarbonyloxymethoxycarbonyl,1-(benzyloxycarbonyloxy)-ethoxycarbonyl,1-(1-phenylethoxycarbonyloxy)-ethoxycarbonyl,1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl,1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl,1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl, cyano, 1H-tetrazolyl,1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl group.

In Compounds According to Option C

R₁ may denote a fluorine, chlorine or bromine atom or a fluoromethyl,difluoromethyl, trifluoromethyl, methyl, ethyl, n-propyl or isopropylgroup,

R₂ may denote the 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl,1-methyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl,1-ethyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl,1-n-propyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl,1-isopropyl-5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl,4,5-dimethyl-oxazol-2-yl, 4-methyl-5-ethyl-oxazol-2-yl,4-methyl-5-n-propyl-oxazol-2-yl, 4-methyl-5-n-butyl-oxazol-2-yl,4-methyl-5-n-pentyl-oxazol-2-yl, 4-methyl-5-phenyl-oxazol-2-yl,4,5-diethyl-oxazol-2-yl, 4-ethyl-5-n-propyl-oxazol-2-yl,4-ethyl-5-n-butyl-oxazol-2-yl, 4-ethyl-5-n-pentyl-oxazol-2-yl,4-ethyl-5-phenyl-oxazol-2-yl, 4,5-di-n-propyl-oxazol-2-yl,4-n-propyl-5-n-butyl-oxazol-2-yl, 4-n-propyl-5-n-pentyl-oxazol-2-yl,4-n-propyl-5-phenyl-oxazol-2-yl, 5-methyl-4-ethyl-oxazol-2-yl,5-methyl-4-n-propyl-oxazol-2-yl, 4,5-diphenyl-oxazol-2-yl,5,6,7,8-tetrahydro-benzoxazol-2-yl, 4,5-dimethyl-thiazol-2-yl,4-methyl-5-ethyl-thiazol-2-yl, 4-methyl-5-n-propyl-thiazol-2-yl,4-methyl-5-phenyl-thiazol-2-yl, 4,5-diethyl-thiazol-2-yl,4-ethyl-5-n-propyl-thiazol-2-yl, 4-ethyl-5-phenyl-thiazol-2-yl,4,5-di-n-propyl-thiazol-2-yl, 4,5-di-n-isopropyl-thiazol-2-yl,4-n-propyl-5-phenyl-thiazol-2-yl, 4,5-diphenyl-thiazol-2-yl,5,6,7,8-tetrahydro-benz-thiazol-2-yl, 4-methyl-oxazolin-2-yl,4-ethyl-oxazolin-2-yl, 4-n-propyl-oxazolin-2-yl,4-isopropyl-oxazolin-2-yl, 4-n-butyl-oxazolin-2-yl,4-isobutyl-oxazolin-2-yl, 4-benzyl-oxazolin-2-yl,4-phenyl-oxazolin-2-yl, 4,4-dimethyl-oxazolin-2-yl,4-methyl-5-phenyl-oxazolin-2-yl, 4,4-dimethyl-5-n-propyl-oxazolin-2-yl,4,5-tetramethylene-oxazolin-2-yl, 4-methyl-imidazolin-2-yl,4,5-dimethyl-imidazolin-2-yl, 4,5-tetramethylene-imidazolin-2-yl,4-methyl-imidazol-2-yl, 4,5-dimethyl-imidazol-2-yl,1,4,5-trimethyl-imidazol-2-yl, 1-ethyl-4,5-dimethyl-imidazol-2-yl,1-n-propyl-4,5-dimethyl-imidazol-2-yl,1-isopropyl-4,5-dimethyl-imidazol-2-yl,1-n-butyl-4,5-dimethyl-imidazol-2-yl,1-isobutyl-4,5-dimethyl-imidazol-2-yl,1-cyclopropyl-4,5-dimethyl-imidazol-2-yl,1-cyclobutyl-4,5-dimethyl-imidazol-2-yl,1-cyclopentyl-4,5-dimethyl-imidazol-2-yl,1-cyclohexyl-4,5-dimethyl-imidazol-2-yl,1-cycloheptyl-4,5-dimethyl-imidazol-2-yl,1-benzyl-4,5-dimethyl-imidazol-2-yl,1-(2-phenyl-ethyl)-4,5-dimethyl-imidazol-2-yl-,1-carboxymethyl-4,5-dimethyl-imidazol-2-yl,3-methoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-ethoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-n-propoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-isopropoxycarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-aminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-methylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-ethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-n-propylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-isopropylamino-carbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-dimethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-diethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-di-n-propylaminocarbonylmethyl-4,5-dimethylimidazol-2-yl,1-diisopropylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-N-methyl-ethylaminocarbonylmethyl-4,5-dimethyl-imidazol-2-yl,1-(2-carboxy-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-methoxycarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-ethoxycarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-n-propoxycarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-isopropoxycarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-aminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-methylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-ethylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-n-propylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-isopropylaminocarbonylethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-dimethylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-diethylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-di-n-propylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-diisopropylaminocarbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-N-methyl-ethylamino-carbonyl-ethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-carboxy-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-methoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-ethoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-n-propoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-isopropoxycarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-aminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-methylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-ethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-n-propylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-isopropylaminocarbonylpropyl)-4,5-dimethyl-imidazol-2-yl,1-(3-dimethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-diethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-di-n-propylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-diisopropylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(3-N-methyl-ethylaminocarbonyl-propyl)-4,5-dimethyl-imidazol-2-yl,1-(2,2,2-trifluoroethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-hydroxyethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-hydroxypropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-hydroxybutyl)-4,5-dimethyl-imidazol-2-yl,1-(2-methoxyethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-methoxypropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-methoxybutyl)-4,5-dimethyl-imidazol-2-yl,1-(2-ethoxyethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-ethoxypropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-ethoxybutyl)-4,5-dimethyl-imidazol-2-yl,1-(2-isopropoxyethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-n-propoxypropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-isopropoxybutyl)-4,5-dimethyl-imidazol-2-yl,1-(2-pyrrolidinoethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-pyrrolidinopropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-pyrrolidinobutyl)-4,5-dimethyl-imidazol-2-yl,1-(2-piperidinoethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-piperidinopropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-piperidinobutyl)-4,5-dimethyl-imidazol-2-yl,1-(2-morpholinoethyl)-4,5-dimethyl-imidazol-2-yl,1-(3-morpholinopropyl)-4,5-dimethyl-imidazol-2-yl,1-(4-morpholinobutyl)-4,5-dimethyl-imidazol-2-yl,1-phenyl-4,5-dimethyl-imidazol-2-yl,1-benzyl-4,5-dimethyl-imidazol-2-yl,1-(1-phenylethyl)-4,5-dimethyl-imidazol-2-yl,1-(2-phenylethyl)-4,5-dimethyl-imidazol-2-yl,1-(1-phenylpropyl)-4,5-dimethyl-imidazol-2-yl,1-(2-phenylpropyl)-4,5-dimethyl-imidazol-2-yl,1-(3-phenylpropyl)-4,5-dimethyl-imidazol-2-yl,1-methyl-4,5-diethyl-imidazol-2-yl, 1,4,5-triethyl-imidazol-2-yl,1-ethyl-4-isopropyl-5-methyl-imidazol-2-yl,1-ethyl-4-isobutyl-5-methyl-imidazol-2-yl,1-n-propyl-4-isopropyl-5-methyl-imidazol-2-yl,1-n-propyl-4-isobutyl-5-methyl-imidazol-2-yl,1,4-diisopropyl-5-methyl-imidazol-2-yl,1-isopropyl-4-isobutyl-5-methyl-imidazol-2-yl,1-(2-dimethylamino-ethyl)-4-isopropyl-5-methyl-imidazol-2-yl,1-(2-dimethylamino-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl,1-(3-dimethylamino-propyl)-4-isopropyl-5-methyl-imidazol-2-yl,1-(3-dimethylamino-propyl)-4-isobutyl-5-methyl-imidazol-2-yl,1,5-dimethyl-4-ethyl-imidazol-2-yl,1,5-dimethyl-4-n-propyl-imidazol-2-yl,1,5-dimethyl-4-isopropyl-imidazol-2-yl,1,5-dimethyl-4-isobutyl-imidazol-2-yl,1,5-dimethyl-4-phenyl-imidazol-2-yl,1-methyl-4,5-diphenyl-imidazol-2-yl, 1-ethyl-4,5-diphenyl-imidazol-2-yl,1-n-propyl-4,5-diphenyl-imidazol-2-yl,1-isopropyl-4,5-diphenyl-imidazol-2-yl,1-carboxymethyl-4,5-diphenyl-imidazol-2-yl,1-methoxycarbonylmethyl-4,5-diphenyl-imidazol-2-yl,1-ethoxycarbonylmethyl-4,5-diphenyl-imidazol-2-yl,4,5-trimethylene-imidazol-2-yl, 1-methyl-4,5-trimethylene-imidazol-2-yl,5,6,7,8-tetrahydro-benzimidazol-2-yl,1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-ethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-n-propyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-isopropyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-n-butyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-isobutyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-n-pentyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-n-hexyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-cyclopropyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-cyclobutyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-cyclopentyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-cyclohexyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-cycloheptyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-carboxymethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-methoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-ethoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-n-propoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-isopropoxycarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-aminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-methylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-ethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-n-propylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-isopropylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-dimethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-diethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-di-n-propylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-diisopropylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-N-methyl-ethylaminocarbonylmethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-carboxy-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-methoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-ethoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-n-propoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-isopropoxycarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-aminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-methylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-ethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-n-propylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-isopropylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-dimethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-diethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-di-n-propylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-diisopropylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-N-methyl-ethylaminocarbonyl-ethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-carboxy-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-methoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-ethoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-n-propoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-isopropoxycarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-aminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-methylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-ethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-n-propylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-isopropylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-dimethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-diethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-di-n-propylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-diisopropylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-N-methyl-ethylaminocarbonyl-propyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-phenyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-benzyl-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(1-phenylethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-phenylethyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(1-phenylpropyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(2-phenylpropyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1-(3-phenylpropyl)-5,6,7,8-tetrahydro-benzimidazol-2-yl,1,3-dimethyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl,1,3-diethyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl,1,3-di-n-propyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl or1,3-dibenzyl-5,6,7,8-tetrahydro-benzimidazolium-2-yl group,

R₃ may denote a methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl,1-methyl-n-propyl, tert.butyl, n-pentyl, 1-methyl-n-butyl,2-methyl-n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio or isobutylthio group and

R₄ may denote a carboxy, cyano, 1H-tetrazolyl,1-triphenylmethyl-tetrazolyl, 2-triphenylmethyl-tetrazolyl,methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl,isopropyloxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl,tert.butyloxycarbonyl, n-pentyloxycarbonyl, isoamyloxycarbonyl,n-hexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl,benzyloxycarbonyl, 1-phenylethyloxycarbonyl, 2-phenylethyloxycarbonyl,3-phenylpropyloxycarbonyl, methoxymethoxycarbonyl, cinnamyloxycarbonyl,acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl,n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl,n-pentanoyloxymethoxycarbonyl, isopentanoyloxy-methoxycarbonyl,pivaloyloxymethoxycarbonyl, n-hexanoyloxymethoxycarbonyl,cyclopentanoyloxy-methoxycarbonyl, cyclohexanoyloxymethoxycarbonyl,phenylacetoxymethoxycarbonyl, 1-phenylpropionyloxymethoxycarbonyl,2-phenylpropionyloxymethoxycarbonyl, 3-phenylbutyryloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl,1-propionyloxyethoxycarbonyl, 1-n-butyryloxyethoxycarbonyl,1-isobutyryloxyethoxycarbonyl, 1-n-pentanoyloxyethoxycarbonyl,1-isopentanoyloxy-ethoxycarbonyl, 1-pivaloyloxyethoxycarbonyl,1-n-hexanoyloxyethoxycarbonyl, 1-cyclopentanoyloxyethoxycarbonyl,1-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl,1-(1-phenylpropionyloxy)-ethoxycarbonyl,1-(2-phenylpropionyloxy)-ethoxycarbonyl,1-(3-phenylbutyryloxy)-ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl,methoxycarbonyloxy-methoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl,n-propyloxycarbonyloxymethoxycarbonyl,isopropyloxycarbonyloxymethoxycarbonyl,n-butyloxycarbonyloxymethoxycarbonyl,isobutyloxycarbonyloxymethoxycarbonyl,tert.butyloxycarbonyloxymethoxycarbonyl,n-pentyloxycarbonyloxymethoxycarbonyl,isoamyloxycarbonyloxymethoxycarbonyl,n-hexyloxycarbonyloxymethoxycarbonyl,cyclopentyloxycarbonyloxymethoxycarbonyl,cyclohexyloxycarbonyloxymethoxycarbonyl,benzyloxycarbonyloxymethoxycarbonyl,1-phenylethoxycarbonyloxymethoxycarbonyl,2-phenylethoxycarbonyloxymethoxycarbonyl,3-phenylpropyloxycarbonyloxymethoxycarbonyl,cinnamyloxycarbonyloxymethoxycarbonyl,1-(methoxycarbonyloxy)-ethoxycarbonyl,1-(ethoxycarbonyloxy)-ethoxycarbonyl,1-(n-propyloxycarbonyloxy)-ethoxycarbonyl,1-(isopropyloxycarbonyloxy)-ethoxycarbonyl,1-(n-butyloxycarbonyloxy)-ethoxycarbonyl,1-(isobutyloxycarbonyloxy)-ethoxycarbonyl,1-(tert.butyloxycarbonyloxy)-ethoxycarbonyl,1-(n-pentyloxycarbonyloxy)-ethoxycarbonyl,1-(isoamyloxycarbonyloxy)-ethoxycarbonyl,1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl,1-(cyclopentyloxy-carbonyloxy)-ethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl,1-(benzyloxycarbonyloxy)-ethoxycarbonyl,1-(1-phenylethoxycarbonyloxy)-ethoxycarbonyl,1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl,1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl,1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl, aminocarbonyl,methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl,di-n-propylaminocarbonyl, diisopropylaminocarbonyl,N-methylethylaminocarbonyl, N-ethyl-isopropylaminocarbonyl or2,5-dihydro-5-oxo-1.2.4-oxadiazol-3-yl group.

In Compounds According to Option D

R₁ may denote, for example, in the 4-position, a fluorine, chlorine orbromine atom, a methyl, ethyl, n-propyl, isopropyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, difluoromethyl ortrifluoromethyl group,

R₂ may denote a phthalimino, homophthalimino,4,4-dimethyl-homophthalimino, 1-oxo-isoindolin-2-yl, 2-oxo-pyrrolidino,2-oxo-piperidino, 2-oxo-hexamethyleneimino, propanesultam-1-yl,butanesultam-1-yl, pentanesultam-1-yl, maleic acid imido,2-methyl-maleic acid imido, 2-phenyl-maleic acid imido,2,3-dimethyl-maleic acid imido, 3-methyl-2-phenyl-maleic acid imido,2,3-diphenyl-maleic acid imido, piperidin-2-yl, piperidin-2-on-1-yl,quinolin-2-yl, isoquinolin-1-yl, isoquinolin-3-yl, pyridin-2-yl,benzimidazol-2-yl, 1-methyl-benzimidazol-2-yl,1-ethyl-benzimidazol-2-yl, 1-n-propyl-benzimidazol-2-yl,1-isopropyl-benzimidazol-2-yl, 1-n-butyl-benzimidazol-2-yl,1-isobutyl-benzimidazol-2-yl, 1-n-pentyl-benzimidazol-2-yl,1-n-hexyl-benzimidazol-2-yl, 1-cyclopropyl-benzimidazol-2-yl,1-cyclobutyl-benzimidazol-2-yl, 1-cyclopentyl-benzimidazol-2-yl,1-cyclohexyl-benzimidazol-2-yl, 5-fluoro-1-methyl-benzimidazol-2-yl,6-fluoro-1-methyl-benzimidazol-2-yl,5-trifluoromethyl-benzimidazol-2-yl,5-trifluoromethyl-1-methyl-benzimidazol-2-yl,imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl,3-chloro-5,6,7,8-tetrahydro-imidazo[1,2- a]pyridin-2-yl,imidazo[1,2-a]pyrimidin -2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[2,1-b]thiazol-6-yl,imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-a]pyrazin-2-yl,imidazo[1,2-b]pyridazin-2-yl, imidazo[4,5-c]pyridin-2-yl, purin-8-yl,imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl,imidazo[4,5-d]pyridazin-2-yl, aminocarbonylamino,methylaminocarbonylamino, dimethylaminocarbonylamino,N-methylaminocarbonyl-methylamino,N-(dimethylaminocarbonyl)-methylamino,N-dimethylaminocarbonyl-ethylamino,N-dimethylaminocarbonylisopropylamino,N-(dimethylaminocarbonyl)-n-pentylamino,N-methylaminocarbonylethylamino, N-methylaminocarbonyl-n-pentylamino,N-methylaminocarbonyl-n-hexylamino, N-methylaminocarbonyl-n-octylamino,N-methylaminocarbonyl-cyclohexylamino, ethylamino-carbonylamino,N-ethylaminocarbonyl-methylamino, N-ethylaminocarbonyl-ethylamino,N-ethylaminocarbonyl-n-hexylamino, N-ethylaminocarbonyl-n-heptylamino,N-ethylaminocarbonyl-cyclohexylamino, diethylaminocarbonylamino,N-(diethylaminocarbonyl)-methylamino,N-(diethylaminocarbonyl)-ethylamino,N-(diethylaminocarbonyl)-n-butylamino,N-(diethylaminocarbonyl)-n-hexylamino,N-(diethylaminocarbonyl)-n-octylamino, isopropylaminocarbonylamino,N-isopropylaminocarbonylmethylamino, n-butylaminocarbonylamino,N-(n-butyl-aminocarbonyl)-methylamino,N-(n-butylaminocarbonyl)ethylamino,N-(n-butylaminocarbonyl)-isopropylamino,N-(n-butylaminocarbonyl)-n-butylamino,N-(n-butylaminocarbonyl)-n-hexylamino,N-(n-butylaminocarbonyl)-cyclohexylamino,N-(di-(n-butyl)-aminocarbonyl)-amino,N-(di-(n-butyl)-aminocarbonyl)-methylamino,N-(di-(n-butyl)-aminocarbonyl)-ethylamino,N-(di-(n-butyl)-aminocarbonyl)-n-butylamino,N-(di-(n-butyl)-aminocarbonyl)-n-hexylamino,N-(n-pentylaminocarbonyl)-methylamino,N-(n-pentylaminocarbonyl)ethylamino,N-(n-hexylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino,n-heptylaminocarbonylamino, n-octylaminocarbonylamino,N-(n-hexylaminocarbonyl)-n-butylamino,N-(n-hexylaminocarbonyl)-n-pentylamino,N-(n-hexylaminocarbonyl)-n-hexylamino,N-(n-hexylaminocarbonyl)-cyclohexylamino,di-(n-hexyl)-aminocarbonylamino,N-(di-(n-hexyl)-aminocarbonyl)-methylamino,N-((n-hexyl)-methylaminocarbonyl)-amino, cyclohexylaminocarbonylamino,N-cyclohexylaminocarbonyl-methylamino,N-cyclohexylaminocarbonyl-ethylamino,N-cyclohexylaminocarbonyl-n-butylamino,N-cyclohexylaminocarbonyl-isobutylamino,N-cyclohexylaminocarbonyl-n-pentylamino,N-cyclohexylaminocarbonyl-n-hexylamino,N-cyclohexylaminocarbonyl-cyclohexylamino,N-(ethyl-cyclohexylaminocarbonyl)-methylamino,N-(propyl-cyclohexylaminocarbonyl)-methylamino,N-(n-butyl-cyclohexylaminocarbonyl)-methylamino,allylaminocarbonylamino, benzylaminocarbonylamino,N-benzylaminocarbonyl-isobutylamino, phenylaminocarbonylamino,pyrrolidinocarbonylamino, pyrrolidinocarbonyl-methylamino,piperidinocarbonylamino, hexamethyleneiminocarbonylamino,morpholinocarbonylamino, 3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-methyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-ethyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-isopropyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-butyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-isobutyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-pentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-n-hexyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-cyclopentyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-cyclohexyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-cycloheptyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3-benzyl-3,4,5,6-tetrahydro-2-pyrimidon-1-yl,3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-n-propyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-isopropyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl,3-(2-phenylethyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl or3-(3-phenylpropyl)-3,4,5,6-tetrahydro-2(1H)-pyrimidon-1-yl group,

R₃ may denote a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert.butyl, n-pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl,cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, n-propoxy orisopropoxy group and

R₄ may denote a hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl,n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl,isobutyloxycarbonyl, tert.butyloxycarbonyl, n-pentyloxycarbonyl,isoamyloxycarbonyl, n-hexyloxycarbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, benzyloxycarbonyl, 1-phenylethyloxycarbonyl,2-phenylethyloxycarbonyl, 3-phenylpropyloxycarbonyl,methoxymethoxycarbonyl, cinnamyloxycarbonyl, acetoxymethoxycarbonyl,propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl,isobutyryloxymethoxycarbonyl, n-pentanoyloxymethoxycarbonyl,isopentanoyloxy-methoxycarbonyl, pivaloyloxymethoxycarbonyl,n-hexanoyloxymethoxycarbonyl, cyclopentanoyloxy-methoxycarbonyl,cyclohexanoyloxymethoxycarbonyl, phenylacetoxymethoxycarbonyl,2-phenylpropionyloxy-methoxycarbonyl,3-phenylpropionyloxymethoxycarbonyl, 4-phenylbutyryloxymethoxycarbonyl,benzoyloxymethoxycarbonyl, 1-acetoxyethoxycarbonyl,1-propionyloxyethoxycarbonyl, 1-n-butyryloxyethoxy-carbonyl,1-isobutyryloxyethoxycarbonyl, 1-n-pentanoyloxyethoxycarbonyl,1-isopentanoyloxyethoxycarbonyl, 1-pivaloyloxyethoxy-carbonyl,1-n-hexanoyloxyethoxycarbonyl, 1-cyclopentanoyloxyethoxycarbonyl,1-cyclohexanoyloxyethoxycarbonyl, 1-phenylacetoxyethoxycarbonyl,1-(1-phenylpropionyloxy)-ethoxycarbonyl,1-(2-phenylpropionyloxy)-ethoxycarbonyl,1-(3-phenylbutyryloxy)ethoxycarbonyl, 1-benzoyloxyethoxycarbonyl,methoxycarbonyloxy-methoxycarbonyl, ethoxycarbonyloxymethoxycarbonyl,n-propyloxycarbonyloxymethoxycarbonyl,isopropyloxycarbonyloxymethoxycarbonyl,n-butyloxycarbonyloxymethoxycarbonyl,isobutyloxycarbonyloxymethoxycarbonyl,tert.butyloxycarbonyloxy-methoxycarbonyl,n-pentyloxycarbonyloxymethoxycarbonyl,isoamyloxycarbonyloxymethoxycarbonyl,n-hexyloxycarbonyloxymethoxycarbonyl,cyclopentyloxycarbonyloxymethoxycarbonyl,cyclohexyloxycarbonyloxymethoxycarbonyl,benzyloxycarbonyloxymethoxycarbonyl,1-phenylethoxycarbonyloxymethoxycarbonyl,2-phenylethoxycarbonyloxymethoxycarbonyl,3-phenylpropyloxycarbonyloxymethoxycarbonyl,cinnamyloxycarbonyloxymethoxycarbonyl,1-(methoxycarbonyloxy)ethoxycarbonyl,1-(ethoxycarbonyloxy)-ethoxycarbonyl,1-(n-propyloxycarbonyloxy)-ethoxycarbonyl,1-(isopropyloxycarbonyloxy)-ethoxycarbonyl,1-(n-butyloxycarbonyloxy)-ethoxycarbonyl,1-(isobutyloxycarbonyloxy)-ethoxycarbonyl,1-(tert.butyloxycarbonyloxy)-ethoxycarbonyl,1-(n-pentyloxycarbonyloxy)-ethoxycarbonyl,1-(isoamyloxycarbonyloxy)-ethoxycarbonyl,1-(n-hexyloxycarbonyloxy)-ethoxycarbonyl,1-(cyclopentyloxycarbonyloxy)-ethoxycarbonyl,1-(cyclohexyloxycarbonyloxy)-ethoxycarbonyl,cyclopentylcarbonyloxymethoxycarbonyl,1-(benzyloxycarbonyloxy)-ethoxycarbonyl,1-(1-phenylethoxycarbonyloxy)-ethoxycarbonyl,1-(2-phenylethoxycarbonyloxy)-ethoxycarbonyl,1-(3-phenylpropyloxycarbonyloxy)-ethoxycarbonyl,1-(cinnamyloxycarbonyloxy)-ethoxycarbonyl, cyano, 1H-tetrazolyl,1-triphenylmethyl-tetrazolyl, 2-triphenylmethyl-tetrazolyl,1-acetoxymethyl-tetrazolyl, 2-acetoxymethyl-tetrazolyl,1-propionyloxymethyl-tetrazolyl, 2-propionyloxymethyltetrazolyl,1-butyryloxymethyl-tetrazolyl, 2-butyryloxymethyl-1-tetrazolyl,1-isobutyryloxymethyl-tetrazolyl, 2-isobutyryloxymethyl-tetrazolyl,1-pivaloyloxymethyltetrazolyl, 2-pivaloyloxymethyl-tetrazolyl,1-ethoxycarbonyloxymethyl-tetrazolyl,2-ethoxycarbonyloxymethyltetrazolyl,1-[1-(ethoxycarbonyloxy)-ethyl]-tetrazolyl,2-[1-(ethoxycarbonyloxy)-ethyl]-tetrazolyl,1-[1-(cyclohexyloxycarbonyloxy)-ethyl]-tetrazolyl or2-[1-(cyclohexyloxycarbonyloxy)-ethyl]-tetrazolyl group.

Preferred compounds or general formula I above are those wherein R₁, R₂,R₃ and R₄ are as set forth below in options A, B, C or D:

Option A

R₁ in the 4-position represents a fluorine, chlorine or bromine atom, aC₁₋₃ -alkyl group, a cycloalkyl, fluoromethyl, difluoromethyl ortrifluoromethyl group and

R₂ represents a C₃₋₅ -alkoxy group substituted in the 3-, 4- or5-position by an imidazolyl group, or R₂ may represent a C₂₋₅ -alkoxygroup substituted in the 2-, 3-, 4- or 5-position by a benzimidazolyl ortetrahydrobenzimidazolyl group,

an acylamino group optionally substituted at the nitrogen atom by a C₁₋₅-alkyl group, wherein the acyl group is a C₂₋₇ -alkanoyl group, a C₂₋₄(alkoxycarbonyl) group, a C₁₋₃ -alkylsulphonyl group or abenzenesulphonyl group,

a phthalimino or homophthalimino group, wherein a carbonyl group in aphthalimino group may be replaced by a methylene group and a methylenein a homophthalimino group may be substituted by one or two alkylgroups,

a 5-, 6- or 7-membered alkyleneimino or alkenyleneimino group,optionally substituted by one or two alkyl groups or by a tetramethyleneor pentamethylene group, wherein a methylene group may be replaced by acarbonyl or sulphonyl group,

a glutaric acid imino group wherein the n-propylene group may beperfluorinated, or may be substituted by one or two alkyl groups or by atetramethylene or pentamethylene group,

a maleic acid imido group optionally mono- or disubstituted by an alkylor phenyl group, whilst the substituents may be identical or different,

an amidino group optionally substituted by one or two C₁₋₄ alkyl groups,

a benzimidazol-2-yl group optionally substituted in the 1-position byC₁₋₆ -alkyl or a cycloalkyl group, whilst the phenyl nucleus of one ofthe abovementioned benzimidazole groups may additionally be substitutedby a fluorine atom or by a methyl or trifluoromethyl group, R₂ mayrepresent an imidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl,imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl,imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or acarbon attached pyrrolidine, piperidine or pyridine ring in which aphenyl group may be condensed onto the pyridine ring via two adjacentcarbon atoms and a methylene group adjacent to the N-atom in apyrrolidine or piperidine ring may be replaced by a carbonyl group,

a carbon attached imidazolyl group optionally substituted in the1-position by a C₁₋₃ -alkyl group or by a benzyl group, and which mayalso be substituted in the carbon skeleton by a C₁₋₃ -alkyl group,

an imidazolidindione group optionally substituted by an alkyl,phenylalkyl, tetramethylene, pentamethylene or hexamethylene group,

a pyridazin-3-one or dihydro-pyridazin-3-one group which may besubstituted in the 2-position by a methyl or benzyl group,

an R₇ --NR₆ --CO--NR₅ -- group wherein

R₅ represents a hydrogen atom, a C₁₋₅ -alkyl group, a cyclohexyl orbenzyl group,

R₆ represents a hydrogen atom, a C₁₋₆ -alkyl group, an allyl,cyclohexyl, benzyl or phenyl group,

R₇ represents a hydrogen atom or a C₁₋₃ -alkyl group or

R₆ and R₇ together with the nitrogen atom between them represent anunbranched C₄₋₆ -alkyleneimino group or a morpholino group or

R₅ and R₆ together represent a C₂₋₃ -alkylene group, or

R₁, in the 5-, 6- or 7-position, represents a fluorine, chlorine orbromine atom, a C₁₋₄ -alkyl or a trifluoromethyl group and

R₂ represents a benzimidazol-2-yl group optionally substituted in the1-position by a C₁₋₆ -alkyl group or by a cycloalkyl group, whilst thephenyl nucleus of one of the abovementioned benzimidazole groups mayadditionally be substituted by a fluorine atom or by a methyl ortrifluoromethyl group, or R₂ may represent animidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl,imidazo[4,5-c]-pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl,imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]-pyridazin-2-yl group, ora carbon attached pyrrolidine, piperidine or pyridine ring in which aphenyl group may be condensed onto the pyridine ring via 2 adjacentcarbon atoms and a methylene group adjacent to the N-atom in apyrrolidine or piperidine ring may be replaced by a carbonyl group, or acarbon attached imidazolyl group optionally substituted in the1-position by a C₁₋₃ alkyl group or by a benzyl group which may also besubstituted in the carbon skeleton by a C₁₋₃ alkyl group,

R₃ represents a C₁₋₅ -alkyl group or a C₃₋₅ -cycloalkyl group and

R₄ represents a carboxy or 1H-tetrazolyl group, whilst, unless otherwisespecified, an alkanoyl, alkyl or alkoxy moiety as mentioned hereinbeforemay in each case contain 1 to 3 carbon atoms and a cycloalkyl moietymentioned above may contain from 3 to 7 carbon atoms,

Option B

R₁ to R₄ are defined as in Option B, above, and R₂ is in the 6-positionof the benzimidazole ring,

Option C

R₁ denotes a fluorine, chlorine or bromine atom, a trifluoromethyl groupor a C₁₋₃ -alkyl group,

R₂ denotes an imidazol-2-yl group optionally substituted in the1-position by the group R_(a), wherein

R_(a) denotes a phenyl group, a phenylalkyl group having 1 to 3 carbonatoms in the alkyl moiety, a C₅₋₇ -cycloalkyl group or a C₁₋₅ -alkylgroup in which the alkyl moiety may additionally be substituted by agroup which can be metabolised into a carboxy group in vivo, atrifluoromethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl,aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group orfrom position 2 by a hydroxy, methoxy, ethoxy, amino, methylamino,dimethylamino, pyrrolidino, piperidino or morpholino group,

a 5,5-spiro-cyclopentano-dihydroimidazol-4-on-2-yl group,

an imidazolium-2-yl group substituted in the 1- and 3-positions bygroups R_(b), which may be identical or different, whilst

R_(b) denotes an alkyl or phenylalkyl group each having 1 to 3 carbonatoms in the alkyl moiety,

an oxazol-2-yl or thiazol-2-yl group, whilst in the abovementionedimidazol-2-yl, imidazolium-2-yl, oxazol-2-yl or thiazol-2-yl moietiesthe 4-, 5-positions may be substituted by a C₁₋₄ -alkyl group or by aphenyl group, wherein the substituents may be identical or different, oran n-butylene bridge may be added via the 4-, 5-positions,

an oxazolin-2-yl or imidazolin-2-yl group substituted by R₈ to R₁₀,wherein an imino group may be additionally substituted by R_(a), wherebyR₈ to R₁₀ and R_(a) each represent a hydrogen atom or an alkyl groupwith 1 to 4 carbon atoms,

R₃ denotes a C₂₋₅ -alkyl group, a C₃₋₅ -cycloalkyl group, an alkoxy oralkylthio group each having 2 to 4 carbon atoms and

R₄ denotes a group which can be metabolised into a carboxy group invivo, a carboxy, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or2-triphenylmethyl-tetrazolyl group,

whilst the expression "a group which can be metabolised into a carboxygroup in vivo" which appears above denotes the esters thereof of theformulae

    --CO--OR',

    --CO--O--(HCR")--O--CO--R'" and

    --CO--O--(HCR")--O--CO--OR'"

wherein

R' denotes a straight-chained or branched C₁₋₄ -alkyl group or a C₅₋₇-cycloalkyl group,

R" denotes a hydrogen atom or a methyl group and

R'" denotes a straight-chained or branched C₁₋₄ -alkyl group or a C₅₋₇-cycloalkyl group,

Option D

R₁ denotes, in the 4-position, a chlorine atom, a C₁₋₃ -alkyl group or atrifluoromethyl group,

R₂ denotes a phthalimino or homophthalimino group, whilst a carbonylgroup in a phthalimino group may be replaced by a methylene group,

a 5-, 6- or 7-membered alkyleneimino group in which a methylene group isreplaced by a carbonyl or sulphonyl group,

a maleic acid imido group optionally mono- or disubstituted by a methylor phenyl group, whilst the substituents may be identical or different,

a benzimidazol-2-yl or 4,5,6,7-tetrahydro-benzimidazol-2-yl groupoptionally substituted in the 1-position by a C₁₋₆ -alkyl group or by acycloalkyl group (whilst the phenyl nucleus of one of theabove-mentioned benzimidazole groups may additionally be substituted bya fluorine atom or a methyl or trifluoromethyl group), animidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-ylimidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl,imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl,imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group or

an R₇ --NR₆ --CO--NR₅ -- group wherein

R₅ denotes a hydrogen atom, a C₁₋₅ -alkyl group, a cyclohexyl or benzylgroup,

R₆ denotes a hydrogen atom, a C₁₋₆ -alkyl group, an allyl, cyclohexyl,benzyl or phenyl group,

R₇ denotes a hydrogen atom or a C₁₋₃ -alkyl group or

R₆ and R₇ together with the nitrogen atom between them denote astraight-chained C₄₋₆ -alkyleneimino group or a morpholino group or

R₅ and R₆ together denote a C₂₋₃ -alkylene group,

R₃ denotes a C₁₋₅ -alkyl group, a C₃₋₅ -cycloalkyl group or a C₂₋₃-alkoxy group and

R₄ denotes a tetrazolyl group substituted in the 1- or 2-position by anR_(a) --CO--O--CH₂ -- group, or an R_(b) --CO--O--(R_(c) CH)--O--CO--,R_(a) O--CO-- or R_(b) O--CO--O--(R_(c) CH)--O--CO-- group, wherein

R_(a) denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, methoxymethyl or cinnamyl group,

R_(b) denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or3-phenylpropyl group and

R_(c) denotes a hydrogen atom or a methyl group,

or, if

(i) R₁ and R₂ are as hereinbefore defined and R₃ denotes an alkoxygroup, R₄ may denote a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group or,if

(ii) R₁ is as hereinbefore defined, R₂ has the meanings givenhereinbefore with the exception of the 1-methyl-benzimidazol-2-yl groupand R₃ denotes a cyclopropyl group, R₄ may represent a carboxy group or,if

(iii) R₁ and R₃ are as hereinbefore defined and R₂ denotes abutanesultam-1-yl group, R₄ may denote a carboxy group or, if

(iv) R₁ is as hereinbefore defined, R₂ denotes a1-methyl-5-fluoro-benzimidazol-2-yl group and R₃ denotes an ethyl group,R₄ may represent a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group.

Particularly preferred compounds of general formula I above are thosewherein R₁, R₂, R₃ and R₄ are as set forth below in options A, B, C orD:

Option A

R₁ in the 4-position represents a chlorine atom, or a C₁₋₃ -alkyl or atrifluoromethyl group and

R₂ represents a C₃₋₅ -alkoxy substituted in the 3-, 4- or 5-position byan imidazolyl group, or R₂ may represent a C₂₋₅ -alkoxy groupsubstituted in the 2-, 3-, 4- or 5-position by a benzimidazolyl ortetrahydrobenzimidazolyl group,

a C₂₋₅ (alkanoyl)amino group or an N-benzenesulphonylmethylamino group,

a phthalimino or homophthalimino group, wherein a carbonyl group in aphthalimino group may be replaced by a methylene group,

a 5-, 6- or 7-membered alkyleneimino group wherein a methylene group isreplaced by a carbonyl or sulphonyl, group,

a glutaric acid imino group wherein the n-propylene group may besubstituted by one or two alkyl groups or by a tetramethylene orpentamethylene group,

a maleic acid imido group optionally mono- or disubstituted by an alkylor phenyl group, whilst the substituents may be identical or different,

a benzimidazol-2-yl group optionally substituted in the 1-position by aC₁₋₆ -alkyl or by a cycloalkyl group, whilst the phenyl nucleus of oneof the abovementioned benzimidazole groups may additionally besubstituted by a fluorine atom or by a methyl or trifluoromethyl group,or R₂ may represent an imidazo[2,1-b]thiazol-6-yl,imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl,imidazo[4,5-c]pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl,imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or acarbon attached pyrrolidine, piperidine or pyridine ring in which aphenyl group may be condensed onto the pyridine ring via two adjacentcarbon atoms and a methylene group adjacent to the N-atom in apyrrolidine or piperidine ring may be replaced by a carbonyl group,

or an imidazol-4-yl group substituted in the 1-position by a C₁₋₃ alkylgroup or by a benzyl group which may also be substituted in the carbonskeleton by a C₁₋₃ alkyl group,

a pyridazin-3-one or dihydro-pyridazin-3-one group which may besubstituted in the 2-position by a methyl or benzyl group,

an R₇ --NR₆ --CO--NR₅ -- group wherein

R₅ represents a hydrogen atom, a C₁₋₅ -alkyl group, a cyclohexyl orbenzyl group,

R₆ represents a hydrogen atom, a C₁₋₆ -alkyl group, an allyl,cyclohexyl, benzyl or phenyl group,

R₇ represents a hydrogen atom or a C₁₋₃ -alkyl group or

R₆ and R₇ together with the nitrogen atom between them represent anunbranched C₄₋₆ -alkyleneimino group or a morpholino group or

R₅ and R₆ together represent a C₂₋₃ -alkylene group, or

R₁, in the 5-, 6- or 7-position, represents a C₁₋₄ -alkyl group or atrifluoromethyl group and

R₂ represents a benzimidazol-2-yl group optionally substituted in the1-position by a C₁₋₆ -alkyl group or by a cycloalkyl group, whilst thephenyl nucleus of one of the abovementioned benzimidazole groups mayadditionally be substituted by a fluorine atom or by a methyl ortrifluoromethyl group, or R₂ may represent animidazo[2,1-b]thiazol-6-yl, imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, imidazo[4,5-b]pyridin-2-yl,imidazo[4,5-c]pyridin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]-pyridazin-2-yl,imidazo[4,5-c]-pyridin-2-yl, purin-8-yl, imidazo[4,5-b]pyrazin-2-yl,imidazo[4,5-c]pyridazin-2-yl or imidazo[4,5-d]pyridazin-2-yl group, or acarbon attached pyrrolidine, piperidine or pyridine ring in which aphenyl group may be condensed onto the pyridine ring via two adjacentcarbon atoms and a methylene group adjacent to the N-atom in apyrrolidine or piperidine ring may be replaced by a carbonyl group, oran imidazol-4-yl group substituted in the 1-position by a C₁₋₃ alkylgroup or by a benzyl group which may also be substituted in the carbonskeleton by a C₁₋₃ alkyl group,

R₃ represents a C₁₋₅ -alkyl group or a C₃₋₅ -cycloalkyl group and

R₄ represents a carboxy or 1H-tetrazolyl group,

Option B

R₁ represents a chlorine atom or a methyl group,

R₂ represents an oxazol-4-yl or thiazol-4-yl group optionallysubstituted in the 2-position by a methyl or phenyl group, or animidazol-4-yl group optionally substituted in the 2-position by a methylgroup and which is substituted in the 1-position

by a C₁₋₇ -alkyl group which itself may be substituted in the 1-, 2-,3-, 4-, 5-, 6- or 7-position by a carboxy, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, dimethylaminocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl or 1-oxido-thiomorpholino-carbonyl group,

by a C₁₋₃ -alkyl group which is substituted in the 2-, 3- or 4-positionby a hydroxy, methoxy, 2-methoxyethoxy, dimethylamino, diethylamino,pyrrolidino, piperidino, morpholino or imidazol-1-yl group,

or by a 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl,2-phenylethyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-methylbenzyl,4-trifluoromethylbenzyl, 3,5-dimethoxybenzyl or 2,2-diphenylethyl group,

R₃ represents a C₂₋₄ -alkyl group, an alkoxy or alkylthio group eachhaving 2 or 3 carbon atoms in the alkyl moiety, a cyclopropyl orcyclobutyl group and

R₄ represents a group which may be converted in vivo into a carboxygroup, or a carboxy or 1H-tetrazolyl group,

Option C

R₁ in the 4-position denotes a fluorine, chlorine or bromine atom, atrifluoromethyl group or a C₁₋₃ -alkyl group,

R₂ is in the 6-position and has the meanings given above with respect tothe preferred compounds, and

R₃ and R₄ are defined as above with respect to the preferred compounds,

Option D

R₁ denotes, in the 4-position, a methyl group,

R₂ denotes an imidazo[1,2-a]pyridin-2-yl,5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,1-methyl-benzimidazol-2-yl, 1-methyl-5-fluoro-benzimidazol-2-yl orbutanesultam-1-yl group,

R₃ denotes a C₂₋₄ -alkyl group, a cyclopropyl group or a C₂₋₃ -alkoxygroup and

R₄ denotes a tetrazolyl group substituted in the 1- or 2-position by anR_(a) --CO--O--CH₂ -- group, or an R_(b) --CO--O--(R_(c) CH)--O--CO--,R_(a) O--CO-- or R_(b) O--CO--O--(R_(c) CH)--O--CO-- group, whilst

R_(a) denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, methoxymethyl or cinnamyl group,

R_(b) denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or3-phenylpropyl group and

R_(c) denotes a hydrogen atom or a methyl group.

Even more preferred are those compounds of general formula I abovewherein R₁, R₂, R₃ and R₄ are as set forth below in options A, B or C:

Option A

R₁ in the 4-position represents a methyl group or a chlorine atom and

R₂ represents a C₃₋₅ -alkoxy group substituted in the 3-, 4- or5-position by an imidazolyl group, or R₂ may represent a C₂₋₅ -alkoxygroup substituted in the 2-, 3-, 4- or 5-position by a benzimidazolyl ortetrahydrobenzimidazolyl group,

a C₂₋₅ (alkanoyl)amino group or an N-benzenesulphonylmethylamino group,

a phthalimino or homophthalimino group, wherein a carbonyl group in aphthalimino group may be replaced by a methylene group,

a 5-, 6- or 7-membered alkyleneimino group, wherein a methylene group isreplaced by a carbonyl or sulphonyl group,

a maleic acid imido group optionally mono- or disubstituted by an alkylor phenyl group, whilst the substituents may be identical or different,

a benzimidazol-2-yl group optionally substituted in the 1-position by aC₁₋₃ -alkyl group, whilst the phenyl nucleus of one of theabovementioned benzimidazole groups may additionally be substituted by afluorine atom, or R₂ may represent an imidazo[1,2-a]-pyridin-2-yl group,5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl or imidazo[2,1-b]thiazol-6-yl group,

an imidazol-4-yl group substituted in the 1-position by a C₁₋₃ alkylgroup,

a pyridazin-3-one or dihydro-pyridazin-3-one group which may besubstituted in the 2-position by a methyl or benzyl group, or

R₁, in the 5-, 6- or 7-position, may represent a methyl group and

R₂ represents a benzimidazol-2-yl group optionally substituted in the1-position by a C₁₋₃ -alkyl group, whilst the phenyl nucleus mayadditionally be substituted by a fluorine atom, or R₂ may represent animidazo[1,2-a]pyridin-2-yl group, an imidazol-4-yl group substituted inthe 1-position by a C₁₋₃ alkyl group,

R₃ represents a C₁₋₅ -alkyl group or a C₃₋₅ -cycloalkyl group and

R₄ represents a carboxy or 1H-tetrazolyl group,

Option B

R₁, R₂ and R₃ are as defined above and

R₄ denotes a carboxy group or a group of formulae

    --CO--OR',

    --CO--O--(HCR")--O--CO--R'" and

    --CO--O--(HCR")--O--CO--OR'"

wherein

R' denotes a straight-chained or branched C₁₋₆ -alkyl group, a C₅₋₇-cycloalkyl group, a benzyl, 1-phenylethyl, 2-phenylethyl,3-phenylpropyl, methoxymethyl or cinnamyl group,

R" denotes a hydrogen atom or a methyl group and

R'" denotes a straight-chained or branched C₁₋₆ -alkyl group, C₅₋₇-cycloalkyl group, a phenyl, benzyl, 1-phenylethyl, 2-phenylethyl or3-phenylpropyl group, or

Option C

R₁ to R₄ are defined as above and R₂ is in the 6-position and denotesone of the imidazolyl groups mentioned above.

Specifically preferred compounds are:

(a)4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimid-azole-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid.

(b)4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl.

(c)4'-[(2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid.

(d)4'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

(e)4'-[(2-n-Propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

(f)4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid, (g)4'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

(h)4'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate,

(i)4'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl-semihydrate,and

(j)4'-[[2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate.

According to the invention, the compounds are obtained by the followingprocesses:

a) Cyclising a compound of general formula ##STR3## wherein R₁ and R₂are defined as hereinbefore,

one of the groups X₁ or Y₁ represents a group of general formula##STR4## and the other group X₁ or Y₁ represents a group of the generalformula ##STR5## wherein R₂ and R₄ are defined as hereinbefore,

R₈ represents a hydrogen atom or an R₃ CO-- group, wherein R₃ is definedas hereinbefore,

Z₁ and Z₂, which may be identical or different, represent optionallysubstituted amino groups or hydroxy or mercapto groups optionallysubstituted by lower alkyl groups or

Z₁ and Z₂ together represent an oxygen or sulphur atom, an optionallyC₁₋₃ -alkyl substituted imino group, or a C₂₋₃ -alkylenedioxy or C₂₋₃-alkylenedithio group,

but one of the groups X₁ or Y₁ must represent a group of general formula##STR6##

The cyclisation is conveniently carried out in a solvent or mixture ofsolvents such as ethanol, isopropanol, glacial acetic acid, benzene,chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,diethyleneglycol-dimethylether, sulpholane, dimethylformamide, tetralineor in an excess of the acylating agent used to prepare the compound ofgeneral formula II, e.g. in the corresponding nitrile, anhydride, acidhalide, ester or amide, e.g. at temperatures between 0° and 250° C., butpreferably at the boiling temperature of the reaction mixture,optionally in the presence of a condensing agent such asphosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuricacid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid,phosphoric acid, polyphosphoric acid, acetic anhydride or optionally inthe presence of a base such as potassium ethoxide or potassiumtert.-butoxide. However, cyclisation may also be carried out without asolvent and/or condensing agent.

However, it is particularly advantageous to carry out the reaction bypreparing a compound of general formula II in the reaction mixture byreducing a corresponding o-nitro-amino compound, optionally in thepresence of a carboxylic acid of general formula R₃ COOH, or byacylation of a corresponding o-diamino compound. When the reduction ofthe nitro group is broken off at the hydroxylamine stage, the N-oxide ofa compound of general formula I is obtained in the subsequentcyclisation. The resulting N-oxide is then converted by reduction into acorresponding compound of general formula I.

The subsequent reduction of the N-oxide of formula I obtained ispreferably carried out in a solvent such as water, water/ethanol,methanol, glacial acetic acid, ethyl acetate or dimethylformamide withhydrogen in the presence of a hydrogenation catalyst such as Raneynickel, platinum or palladium/charcoal, with metals such as iron, tin orzinc in the presence of an acid such as acetic, hydrochloric orsulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride orsodium dithionite, or with hydrazine in the presence of Raney nickel attemperatures between 0° and 50° C., but preferably at ambienttemperature.

b) Reaction of a benzimidazole of general formula ##STR7## wherein R₁ toR₃ are defined as hereinbefore, with a biphenyl compound of generalformula ##STR8## wherein R₄ is defined as hereinbefore and

Z₃ represents a nucleophilic leaving group such as a halogen atom, e.g.a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group,e.g. a methanesulphonyloxy, phenylsulphonyloxy or p-toluenesulphonyloxygroup.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as methylene chloride, diethylether, tetrahydrofuran,dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionallyin the presence of an acid binding agent such as sodium carbonate,potassium carbonate, sodium hydroxide, potassium tert.-butoxide,triethylamine or pyridine, whilst the latter two may simultaneously alsobe used as solvent, preferably at temperatures between 0° and 100° C.,e.g. at temperatures between ambient temperature and 50° C.

In the reaction, a mixture of the 1- and 3- isomers is preferablyobtained which can if desired subsequently be resolved into thecorresponding 1- and 3- isomers, preferably by chromatography using asubstrate such as silica gel or aluminium oxide.

c) In order to prepare a compound of general formula I wherein R₄represents a carboxy group:

Converting a compound of general formula: ##STR9## wherein R₁ to R₃ aredefined as hereinbefore and

R₄ ' represents a group which may be converted into a carboxy group byhydrolysis, thermolysis or hydrogenolysis.

For example, functional derivatives of the carboxy group such asunsubstituted or substituted amides, esters, thiolesters, orthoesters,iminoethers, amidines or anhydrides, a nitrile group or a tetrazolylgroup may be converted into a carboxy group by hydrolysis, esters withtertiary alcohols, e.g. tert.butylester, may be converted into a carboxygroup by thermolysis and esters with aralkanols, e.g. benzylester, maybe converted into a carboxy group by hydrogenolysis.

The hydrolysis is conveniently carried out in the presence of an acidsuch as hydrochloric, sulphuric, phosphoric, trichloroacetic ortrifluoroacetic acid in the presence of a base such as sodium hydroxideor potassium hydroxide in a suitable solvent such as water,water/methanol, ethanol, water/ethanol, water/isopropanol orwater/dioxane at temperatures between -10° C. and 120° C., e.g. attemperatures between ambient temperature and the boiling temperature ofthe reaction mixture. When hydrolysis is carried out in the presence ofan organic acid such as trichloroacetic or trifluoroacetic acid, anyalcoholic hydroxy groups present may optionally be simultaneouslyconverted into a corresponding acyloxy group such as a trifluoroacetoxygroup.

If R₄ ' in a compound of general formula V represents a cyano oraminocarbonyl group, these groups may also be converted into a carboxygroup with a nitrite, e.g. sodium nitrite, in the presence of an acidsuch as sulphuric acid, which may also be simultaneously used assolvent, at temperatures between 0° and 50° C.

If R₄ ' in a compound of general formula V represents, for example, atert.-butyloxycarbonyl group, the tert.-butyl group may also bethermally cleaved, optionally in an inert solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane andpreferably in the presence of a catalytic amount of an acid such asp-toluenesulphonic acid, sulphuric, phosphoric or polyphosphoric acid,preferably at the boiling temperature of the solvent used, e.g. attemperatures between 40° C. and 100° C.

If R₄ ' in a compound of general formula V represents, for example, abenzyloxycarbonyl group, the benzyl group may also be hydrogenolyticallycleaved in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide, preferably at temperatures between 0° and 50° C. ,e.g. at ambient temperature, under a hydrogen pressure of 1 to 5 bar.During hydrogenolysis, other groups may be reduced at the same time,e.g. a nitro group may be reduced to an amino group, a benzyloxy groupto a hydroxy group, a vinylidene group to the corresponding alkylidenegroup or a cinnamic acid group to the corresponding phenyl-propionicacid group, or they may be replaced by hydrogen atoms, e.g. a halogenmay be replaced by a hydrogen atom.

d) In order to prepare a compound of general formula I wherein R₄represents a 1H-tetrazolyl group:

Cleaving of a protective group from a compound of general formula##STR10## wherein R₁, R₂ and R₃ are defined as hereinbefore and

R₄ " represents a 1H-tetrazolyl group protected in the 1- or 3-positionby a protecting group.

Suitable protecting groups include, for example, triphenylmethyl,tributyl tin or triphenyl tin groups.

The cleaving of a protective group used is preferably carried out in thepresence of a hydrohalic acid, preferably in the presence ofhydrochloric acid, in the presence of a base such as sodium hydroxide oralcoholic ammonia, in a suitable solvent such as methylene chloride,methanol, methanol/ammonia, ethanol or isopropanol at temperaturesbetween 0° and 100° C., but preferably at ambient temperature or, if thereaction is carried out in the presence of alcoholic ammonia, atelevated temperatures, e.g. at temperatures between 100° and 150° C.,preferably at temperatures between 120° and 140° C.

e) In order to prepare a compound of general formula I wherein R₄represents a 1H-tetrazolyl group:

Reaction of a compound of general formula ##STR11## wherein R₁ to R₃ aredefined as hereinbefore, with hydrazoic acid or the salts thereof.

The reaction is preferably carried out in a solvent such as benzene,toluene or dimethylformamide at temperatures between 80° and 150° C.,preferably at 125° C. Conveniently, either the hydrazoic acid isliberated during the reaction from an alkali metal azide, e.g. sodiumazide, in the presence of a weak acid such as ammonium chloride or atetrazolide salt obtained in the reaction mixture during the reactionwith a salt of hydrazoic acid, preferably with aluminium azide ortributyl tin azide, which is also preferably produced in the reactionmixture by reacting aluminium chloride or tributyl tin chloride with analkali metal azide such as sodium azide, is subsequently liberated byacidification with a dilute acid such as 2N hydrochloric or 2N sulphuricacid.

f) In order to prepare compounds of general formula I wherein R₂represents one of the above-mentioned imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-c]pyrimidin-2-yl,imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-b]pyridazin-2-yl orimidazo[2,1-b]-thiazol-6-yl groups:

Reaction of a compound of general formula ##STR12## wherein one of thegroups A₁, A₂, A₃ or A₄ represents a methine group or a nitrogen atomand

the remaining groups A₁, A₂, A₃ or A₄ represent methine groups or A₁ andA₂ each represent a methine group and the --A₃ ═A₄ -- group represents asulphur atom,

R₉ represents a hydrogen, fluorine, chlorine or bromine atom, an alkyl,alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino,alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl,aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group and

R₁₀ represents a hydrogen, fluorine or chlorine atom, or a methyl,methoxy or hydroxy group, whilst if R₉ and R₁₀ represent adjacent methylgroups these may be linked together by a methylene or ethylene group,with a compound of general formula ##STR13## wherein R₁, R₃ and R₄ aredefined as hereinbefore and

Z₄ represents a nucleophilic leaving group such as a halogen atom, e.g.a chlorine or bromine atom.

The reaction is expediently carried out in a solvent or mixture ofsolvents such as ethanol, isopropanol, benzene, glycol,glycolmonomethylether, dimethyl-formamide or dioxane, e.g. attemperatures between 0° and 150° C. preferably, at temperatures between20° and 100° C. However, the reaction may also be carried out withoutsolvents.

g) In order to prepare compounds of general formula I wherein R₂represents one of the above-mentioned benzimidazol-2-yl,imidazo[4,5-b]pyridin-2-yl, imidazo[4,5-c]pyridin-2-yl,imidazo[4,5-b]pyrazin-2-yl, imidazo[4,5-c]pyridazin-2-yl,imidazo[4,5-d]pyridazin-2-yl or purin-8-yl groups:

Cyclisation of a compound of general formula ##STR14## wherein none, oneor two of the groups A₅, A₆, A₇ or A₈ represent a nitrogen atom and

the remaining groups A₅, A₆, A₇ or A₈ represent methine groups,

R₁₁ represents a hydrogen, fluorine, chlorine or bromine atom or analkyl, alkoxy, hydroxy, phenyl, nitro, amino, alkylamino, dialkylamino,alkanoylamino, cyano, carboxy, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, alkanoyl,aminosulphonyl, alkylaminosulphonyl or dialkylamino-sulphonyl group and

R₁₂ represents a hydrogen, fluorine or chlorine atom or a methyl,methoxy or hydroxy group,

one of the groups X₂ or Y₂ represents an R₁₃ --NH-- group and the otherX₂ or Y₂ group represents a group of general formula ##STR15## whereinR₁, R₃ and R₄ are defined as hereinbefore, one of the groups R₁₃ or R₁₄represents a hydrogen atom and the other R₁₃ or R₁₄ group represents ahydrogen atom, a C₁₋₆ -alkyl group or a cycloalkyl group,

Z₅ and Z₆, which may be identical or different, represent optionallysubstituted amino groups or hydroxy or mercapto groups optionallysubstituted by lower alkyl groups or Z₅ and Z₆ together represent anoxygen or sulphur atom, an optionally C₁₋₃ -alkyl substituted iminogroup, or an alkylenedioxy or alkylenedithio group each having 2 or 3carbon atoms, optionally with subsequent hydrolysis.

The cyclisation is conveniently carried out in a solvent or mixture ofsolvents such as ethanol, isopropanol, glacial acetic acid, benzene,chlorobenzene, toluene, xylene, glycol, glycolmonomethylether,diethyleneglycol-dimethylether, sulpholan, dimethylformamide, tetralinor in an excess of the acylating agent used to prepare the compound ofgeneral formula X, e.g. in the corresponding nitrile, anhydride, acidhalide, ester or amide, e.g. at temperatures between 0° and 250° C., butpreferably at the boiling temperature of the reaction mixture,optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid,p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid,phosphoric acid, polyphosphoric acid, acetic acid anhydride oroptionally in the presence of a base such as potassium ethoxide orpotassium tert.-butoxide. However, the cyclisation may also be carriedout without a solvent and/or condensing agent.

However, it is particularly advantageous to perform the reaction bypreparing a compound of general formula X in the reaction mixture byreducing a corresponding o-nitro-amino compound, optionally in thepresence of a carboxylic acid of general formula ##STR16## wherein R₁,R₃ and R₄ are defined as hereinbefore, or by acylating a correspondingo-diamino compound with a carboxylic acid of general formula XI.

When the reduction of the nitro group is broken off at the hydroxylaminestage, subsequent cyclisation produces the N-oxide of a compound ofgeneral formula I. The N-oxide thus obtained is then converted byreduction into a corresponding compound of general formula I.

The subsequent reduction of an N-oxide thus obtained is preferablycarried out in a solvent such as water, water/ethanol, methanol, glacialacetic acid, ethyl acetate or dimethylformamide with hydrogen in thepresence of a hydrogenation catalyst such as Raney nickel, platinum orpalladium/charcoal, with metals such as iron, tin or zinc in thepresence of an acid such as acetic, hydrochloric or sulphuric acid, withsalts such as iron(II)sulphate, tin(II)chloride or sodium dithionite, orwith hydrazine in the presence of Raney nickel at temperatures between0° and 50° C., but preferably at ambient temperature.

The subsequent hydrolysis is conveniently carried out either in thepresence of an acid such as hydrochloric, sulphuric, phosphoric,trichloroacetic or trifluoroacetic acid in the presence of a base suchas sodium hydroxide or potassium hydroxide in a suitable solvent such aswater, water/methanol, ethanol, water/ethanol, water/isopropanol orwater/dioxane at temperatures between -10° C. and 120° C., e.g. attemperatures between ambient temperature and the boiling temperature ofthe reaction mixture. When hydrolysis is carried out in the presence ofan organic acid such as trichloroacetic or trifluoroacetic acid, anyalcoholic hydroxy groups present may simultaneously be converted into acorresponding acyloxy group such as the trifluoroacetoxy group.

h) In order to prepare compounds of general formula I wherein R₂represents a dihydro-pyridazin-3-one or pyridazin-3-one group which maybe substituted in the 2-position by an optionally phenyl-substitutedC₁₋₃ -alkyl group or in the carbon structure by one or two C₁₋₃ -alkylgroups:

Reaction of a carboxylic acid of general formula ##STR17## wherein R₁,R₃ and R₄ are defined as hereinbefore and

E represents an ethylene or ethenylene group optionally substituted byone or two C₁₋₃ -alkyl groups, or the reactive acid derivatives thereofsuch as the esters, amides or halides thereof, with a hydrazine ofgeneral formula

    H.sub.2 N--NHR.sub.15                                      (XlII)

wherein

R₁₅ represents a hydrogen atom or an optionally phenyl-substituted C₁₋₃-alkyl group.

The reaction is conveniently carried out in a solvent such as methanol,ethanol, isopropanol, glacial acetic acid or propionic acid and/or in anexcess of the hydrazine or hydrazine hydrate used at temperaturesbetween 0° and 200° C., e.g. at temperatures between 20° and 150° C.,but preferably at the boiling temperature of the reaction mixture, andoptionally in the presence of an acid such as sulphuric orp-toluenesulphonic acid as condensing agent. The reaction may, however,also be carried out without a solvent.

i) In order to prepare compounds of general formula I wherein R₂ denotesan oxazol-2-yl, thiazol-2-yl or imidazol-2-yl group, in which ann-butylene bridge is added via the 4,5-positions and additionally theimino group in the imidazole ring may be substituted by a C₁₋₆ -alkylgroup, by a phenylalkyl group having 1 to 3 carbon atoms in the alkylmoiety or by a phenyl group:

Reaction of a compound of general formula ##STR18## wherein R₁, R₃ andR₄ are as hereinbefore defined and

X denotes an oxygen or sulphur atom or an imino group optionallysubstituted by a C₁₋₆ -alkyl group, by a phenylalkyl group having 1 to 3carbon atoms in the alkyl moiety or by a phenyl group, with anα-haloketone of general formula ##STR19## wherein Z₇ denotes a halogenatom such as a chlorine atom.

The reaction is preferably carried out in the presence of a suitablesolvent such as dimethylformamide, diethyleneglycol-dimethylether,triethyleneglycoldimethyl-ether or sulpholane, optionally in thepresence of a base such as potassium carbonate, pyridine, triethylamine,N-ethyl-diisopropylamine or N-ethyl-dicyclohexylamine, at temperaturesbetween 0° and 250° C.

If X denotes an oxygen or sulphur atom, the reaction is preferablycarried out in a solvent having a boiling point above 150° C. or in amelt at temperatures between 150° and 250° C., preferably attemperatures between 175° and 225° C.

If X denotes an optionally alkyl-substituted imino group the reaction ispreferably carried out in the presence of a corresponding amine assolvent, e.g. in the presence of liquid ammonia, methylamine,ethylamine, n-propylamine or isopropylamine, at temperatures between 0°and 100° C., preferably at temperatures between 20° and 75° C.

j) In order to prepare compounds of general formula Z wherein R₂ denotesone of the imidazol-2-yl groups mentioned hereinbefore:

Reaction of a compound of general formula ##STR20## wherein R₁, R₃ andR₄ are as hereinbefore defined and

R₂ ' denotes one of the above-mentioned oxazol-2-yl groups, with anamine of general formula

    H.sub.2 N--R.sub.16                                        (XVII)

wherein

R₁₆ has the meanings given for R_(a) hereinbefore or denotes a hydrogenatom.

The reaction is expediently carried out in an excess of the amine usedand preferably in the presence of a corresponding formamide of formulaHCONHR₁₆ as solvent, optionally in a pressurised vessel at elevatedtemperatures, e.g. at temperatures between 100° and 250° C., preferablyat temperatures between 175° and 225° C.

During the reaction, any substituted carboxy group present in the groupR₄ is simultaneously converted into the carboxy group or any substitutedtetrazolyl group present is converted into the 1H-tetrazol-5-yl group.

k) In order to prepare compounds of general formula I wherein R₂ denotesa 5,5-spiro-cyclopentano-dihydro-imidazol-4-on-2-yl group:

Treating a benzimidazole of general formula ##STR21## wherein R₁, R₃ andR₄ are as hereinbefore defined and

R₂ " denotes an imidazol-2-yl group in which an n-butylene group isattached via the 4,5-positions, with a base in the presence of air andlight.

The reaction is carried out in the presence of a base such as sodiumhydroxide or potassium hydroxide, in a suitable solvent such as water,water/methanol, ethanol, water/ethanol, water/isopropanol orwater/dioxane, at temperatures between -10° C. and 120° C., e.g. attemperatures between ambient temperature and the boiling temperature ofthe reaction mixture.

During the reaction any ester group present in the group R₄ issimultaneously converted into a carboxy group.

In order to prepare compounds of general formula I wherein R₂ denotesone of the above-mentioned imidazol-2-yl groups which may be substitutedin the 1-position by a phenylalkyl group (whilst the phenyl nucleus maybe mono- or disubstituted by alkyl, hydroxy or alkoxy groups and thesubstituents may be identical or different), or by a C₁₋₆ -alkyl group,whilst the alkyl group may additionally be substituted by a group whichcan be metabolised into a carboxy group in vivo, or by atrifluoromethyl, carboxyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl or dialkylaminocarbonyl group, or R₂ denotes one ofthe imidazolium-2-yl groups mentioned hereinbefore:

Reacting a compound of general formula ##STR22## wherein R₁ and R₃ areas hereinbefore defined,

R₂ '" represents one of the imidazol-2-yl groups unsubstituted in the1-position mentioned hereinbefore and

R₄ '" denotes a carboxy group or a group which can be converted into acarboxy group by hydrolysis, thermolysis or hydrogenolysis, or a1H-tetrazolyl or 2H-tetrazolyl group protected by a protecting group,with a compound of general formula

    Z.sub.8 --R.sub.17                                         (XX)

wherein

R₁₇ denotes a phenylalkyl group, whilst the phenyl nucleus may be mono-or disubstituted by alkyl, hydroxy or alkoxy groups and the substituentsmay be identical or different, or a C₁₋₆ -alkyl group, whilst the alkylgroup may additionally be substituted by a group which can bemetabolised in vivo into a carboxy group, or by a trifluoromethyl,carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl ordialkylaminocarbonyl group, and

Z₈ denotes a nucleophilic leavig group such as a halogen atom, e.g. achlorine, bromine or iodine atom, and subsequently, if necessary,cleaving the protecting groups used.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as methylene chloride, diethylether, tetrahydrofuran,dioxane, dimethylsulphoxide, dimethylformamide or benzene optionally inthe presence of an acid binding agent, such as sodium carbonate,potassium carbonate, sodium hydroxide, sodium hydride, potassiumtert.butoxide, triethylamine or pyridine, whilst the latter two maysimultaneously be used as solvents, preferably at temperatures between0° and 100° C., e.g. at temperatures between ambient temperature and 50°C.

If the reaction is carried out in the presence of an excess of thecompound of formula XX used, a corresponding imidazolium-2-yl compoundof general formula I is obtained at the same time.

The subsequent cleaving of a protecting group is preferably carried outby hydrolysis, thermolysis or hydrogenolysis.

The hydrolytic cleaving of a protecting group used is preferably carriedout in the presence of an acid such as hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, trichloroacetic acid ortrifluoroacetic acid, optionally in the presence of a reactionaccelerator such as hexadecyltributyl-phosphonium bromide in a suitablesolvent such as water, water/methanol, ethanol, water/ethanol,water/isopropanol or water/dioxane at temperatures between -10° C. and120° C., e.g. at temperatures between ambient temperature and theboiling temperature of the reaction mixture.

The thermolytic cleaving of a protecting group such as thetert.butyloxycarbonyl group is preferably effected in an inert solventsuch as methylene chloride, chloroform, benzene, toluene,tetrahydrofuran or dioxane and preferably in the presence of a catalyticamount of an acid such as p-toluenesulphonic acid, sulphuric acid,phosphoric acid or polyphosphoric acid, preferably at the boilingtemperature of the solvent used, e.g. at temperatures between 40° C. and100° C.

The hydrogenolytic cleaving of a protecting group such as thebenzyloxycarbonyl group is effected in the presence of a hydrogenationcatalyst such as palladium/charcoal in a suitable solvent such asmethanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate,dioxane or dimethylformamide, preferably at temperatures between 0° and50° C., e.g. at ambient temperature, and a hydrogen pressure of 1 to 5bar.

m) In order to prepare compounds of general formula I wherein R₂represents one of the imidazol-2-yl groups mentioned hereinbeforesubstituted by the groups R₁₈ to R₂₀, but R₁₉ or R₂₀ must denote ahydrogen atom:

Reacting an aminoketone of general formula ##STR23## wherein R₁, R₃, R₄and R₁₈ to R₂₀ are as hereinbefore defined, but R₁₉ or R₂₀ must denote ahydrogen atom, and

R_(a) ' has the meanings given for R_(a) hereinbefore or denotes ahydrogen atom, with an ammonium salt of a lower aliphatic carboxylicacid.

The reaction is carried out with an ammonium salt of a lower aliphaticcarboxylic acid such as ammonium acetate or ammonium propionate,preferably in the presence of a solvent such as glacial acetic acid orpropionic acid at elevated temperatures, but preferably at the boilingtemperature of the reaction mixture, e.g. at temperatures between 100°and 150° C.

n) In order to prepare compounds of general formula I wherein R₂ denotesone of the oxazolin-2-yl or imidazolin-2-yl groups as hereinbeforedefined:

Dehydrating a compound of general formula ##STR24## wherein R₁, R₃, R₄and R₁₈ to R₂₀ are as hereinbefore defined and

Y denotes a hydroxy or NHR_(a) group, wherein R_(a) is as hereinbeforedefined.

The dehydration is carried out in the presence of a dehydrating agentsuch as phosphorusoxychloride, sulphuric acid, polyphosphoric acid orthionyl chloride, the latter preferably being used as solvent at thesame time, at elevated temperatures, e.g. at the boiling temperature ofthe dehydrating agent used, e.g. at temperatures between 105° and 150°C.

o) In order to prepare compounds of general formula I wherein R₂ denotesone of the imidazolin-2-yl groups as hereinbefore defined:

Reacting a compound of general formula ##STR25## wherein R₁, R₃ and R₄are as hereinbefore defined and

R₂ "" denotes one of the oxazolin-2-yl groups mentioned for R₂hereinbefore, substituted by groups R₈ to R₁₀, with an amine of generalformula

    H.sub.2 N--(R.sub.18 CH)--(R.sub.19 CR.sub.20)--NH.sub.2   (XXIV)

wherein

R₁₈ to R₂₀ are as hereinbefore defined.

The reaction is conveniently carried out in a solvent such as toluene,dimethylformamide or dimethylsulphoxide, but preferably in an excess ofthe amine of general formula XXIV used, at elevated temperatures, e.g.at temperatures between 100° and 150° C. However, the reaction ispreferably carried out without a solvent.

p) In order to prepare compounds of general formula I wherein R₂ denotesone of the oxazol-2-yl groups mentioned hereinbefore substituted bygroups R₁₈ to R₂₀ :

Dehydrating an aminoketone of general formula ##STR26## wherein R₁, R₃,R₄ and R₁₈ to R₂₀ are as hereinbefore defined, but R₁₉ or R₂₀ mustdenote a hydrogen atom, with an ammonium salt of a lower aliphaticcarboxylic acid.

The dehydration is carried out in the presence of a dehydrating agentsuch as phosphorusoxychloride, phosphoric acid or sulphuric acid, whichis preferably used as solvent at the same time, at elevatedtemperatures, e.g. at the boiling temperature of the dehydrating agentused, e.g. at temperatures between 105° and 150° C. During the reactionwith phosphorusoxychloride any tert.butylester present at the same timecan be cleaved.

q) In order to prepare compounds of general formula I wherein R₂ denotesone of the imidazol-2-yl groups mentioned hereinbefore, substituted bythe groups R₁₈ to R₂₀ :

Dehydrogenating a compound of general formula ##STR27## wherein R₁, R₃and R₄ are as hereinbefore defined and

R₂ '"" denotes one of the imidazolin-2-yl groups mentioned for R₂hereinbefore, substituted by the groups R₁₈ to R₂₀, but R₁₉ or R₂₀ mustdenote a hydrogen atom.

The dehydrogenation is carried out in the presence of a dehydrogenatingagent such as palladium/charcoal, barium manganate or selenium dioxide,in a suitable solvent such as toluene or methylene chloride at elevatedtemperatures, e.g. at the boiling temperature of the solvent used, e.g.at temperatures between 110° and 150° C.

r) In order to prepare compounds of general formula I wherein R₄ denotesa 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl group:

Reacting an optionally in the reaction mixture prepared amidoxime ofgeneral formula ##STR28## wherein R₁ to R₃ are as hereinbefore defined,with a compound of general formula

    Z.sub.9 --CO--OR.sub.21                                    (XXVIII)

wherein

Z₉ denotes a nucleophilic leaving group such as a halogen atom, e.g. achlorine, bromine or iodine atom, and

R₂₁ denotes an alkyl, aryl or aralkyl group, preferrably a lower alkylgroup such as the methyl, ethyl, n-propyl or isopropyl group, andsubsequently cyclisizing a thus obtained acylated amidoxime.

The reaction is conveniently carried out in a solvent such as methylenechloride, chloroform, tetrahydrofuran, dioxane or acetonitrilepreferrably in the presence of an inorganic base such as sodium orpotassium carbonate or of an organic base such as triethylamine orpyridine whilst the latter two may simultaneously also be used assolvent at temperatures between 0° and 20° C.

The subsequent cyclization of a thus obtained acylated amidoxime isconveniently carried out in an organic solvent such as benzene, toluene,xylene, tetrahydrofuran or dioxane at elevated temperatures, e.g. attemperatures between 50° and 100° C., preferrably at the boilingtemperature of the solvent used.

The necessary starting amidoxime is prepared conveniently by reaction ofa corresponding nitrile with hydroxylamine in the presence of a solventsuch as methanol, ethanol, methylene chloride, chloroform,dimethylformamide, tetrahydrofuran or dioxane in the presence of asuitable base such as sodium carbonate, potassium carbonate, sodiumhydroxide, triethylamine, sodium methoxide, sodium ethoxide or sodiumhydride at temperatures between 50° and 100° C.

s) In order to prepare a compound of general formula I wherein R₄denotes a tetrazolyl group substituted in the 1- or 2-position by anR_(a) --CO--O--CH₂ -- group, or it denotes an R_(a) O--CO--, R_(b)--CO--O--(R_(c) CH)--O--CO-- or R_(b) O--CO--O--(R_(c) CH)--O--CO--group:

Reacting a compound of general formula ##STR29## wherein R₁ to R₃ are ashereinbefore defined and

R₄ "" denotes a carboxy, 1H-tetrazolyl or 2H-tetrazolyl group, with acompound of general formula

    Z.sub.10 --Y.sub.3                                         (XXX)

wherein

Y₃ denotes an R_(a) --CO--O--CH₂ --, R_(b) --CO--O--(R_(c) CH)--, R_(b)O--CO--O--(R_(c) CH)-- or R_(a) -group, wherein R_(a) to R_(c) are ashereinbefore defined and

Z₁₀ denotes a nucleophilic leaving group such as a halogen atom, e.g. achlorine or bromine atom, or, if Y denotes an R_(a) -group, Z₁₀ may alsorepresent a hydroxy group.

The reaction is conveniently carried out by esterification with acorresponding alcohol or with a corresponding reactive derivative suchas the halide, conveniently in a solvent or mixture of solvents such aswater, methylene chloride, chloroform, ether, tetrahydrofuran, dioxaneor dimethylformamide or in an excess of the acylating agent as solvent,optionally in the presence of an acid activating or dehydrating agentsuch as thionylchloride, with the anhydrides, esters or halides thereofoptionally in the presence of an inorganic or tertiary organic base suchas sodium hydroxide, potassium carbonate, triethylamine or pyridine,whilst the latter two may simultaneously be used as solvent, attemperatures between -25° and 100° C., but preferably at temperaturesbetween -10° and 80° C.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, amino or alkylamino groups may be protected during thereaction by conventional protecting groups which are split off againafter the reaction.

Examples of protecting groups for a hydroxy group are trimethylsilyl,acetyl, benzoyl, methyl, ethyl, tert.-butyl, benzyl andtetrahydropyranyl groups and protecting groups for an amino, alkylaminoor imino group include the acetyl, benzoyl, ethoxycarbonyl and benzylgroups.

The optional subsequent cleaving of a protecting group is preferablycarried out by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as hydrochloric or sulphuric acid or in thepresence of an alkali metal base such as sodium hydroxide or potassiumhydroxide at temperatures between 0° and 100° C., preferably at theboiling temperature of the reaction mixture. However, a benzyl group ispreferably split off by hydrogenolysis, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0° and 50° C., but preferably at ambient temperature, under ahydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

An isomer mixture of a compound of general formula I thus obtained mayif desired be resolved by chromatography using a substrate such assilica gel or aluminium oxide.

Moreover, the compounds of general formula I obtained may be convertedinto the acid addition salts thereof, more particularly forpharmaceutical use the physiologically acceptable salts thereof withinorganic or organic acids. Suitable acids for this purpose includehydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic,lactic, citric, tartaric or maleic acid.

Furthermore, the new compounds of general formula I thus obtained, ifthey contain a carboxy or 1H-tetrazolyl group, may if desiredsubsequently be converted into the salts thereof with inorganic ororganic bases, more particularly for pharmaceutical use into thephysiologically acceptable addition salts thereof. Suitable basesinclude for example sodium hydroxide, potassium hydroxide,cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulae II to XXX used as starting materialsare, in some cases, known from the literature, or may be obtained bymethods known from the literature.

Thus, for example, a compound of general formula II is obtained byalkylation of a corresponding o-amino-nitro compound with a compound ofgeneral formula IV and subsequent reduction of the nitro group.

A compound of general formula III, V, VI, VII, IX, X, XII, XIV, XVI,XVIII, XIX or XXIX used as starting material is obtained by acylation ofa corresponding o-phenylenediamine or a corresponding o-amino-nitrocompound, followed by reduction of the nitro group and subsequentcyclisation of an o-diaminophenyl compound thus obtained, optionallyfollowed by the cleaving of any protecting group used or by cyclisationof a correspondingly substituted benzimidazole with a correspondingamine or by NH-alkylation of a corresponding 1H-benzimidazole, whilstthe isomer mixture thus obtained may subsequently be resolved byconventional methods, e.g. chromatography. Some of the startingcompounds mentioned above are described in EP-A-0 392 317. Before thereduction of the nitro group an oxazol-4-yl compound thus obtained maybe converted into the corresponding imidazol-4-yl compound by means of acorresponding amine, preferably with ammonia, under pressure, or animidazol-4-yl compound unsubstituted in the 1-position obtained in thisway may be converted by alkylation into a corresponding imidazol-4-ylcompound alkylated in the 1-position.

The conversions of oxazol-2-yl compounds into imidazol-2-yl compoundssubstituted in the 1-position, as described in this application, arecarried out analogously to the synthesis of 1H-imidazole described inAngew. Chem. 71, 761 (1959) (conversion of oxazoles into 1H-imidazolesusing formamide/ammonia), whereby the oxazoles can be prepared byacylation of a corresponding α-aminoketone with a correspondingcarboxylic acid chloride or carboxylic acid anhydride followed bycyclisation analogously to J. Chem. Soc. 95, 2167 (1909) and Synthesis1970, 648, using as condensation agents strong acids such as sulphuricacid, phosphoric acid, hydrofluoric acid or POCl₃.

For example, 2-n-propyl-5-(imidazo[1,2-a]pyridin-2-yl)-3H-benzimidazoleis obtained by reacting p-amino-acetophenone with butyric acid chloride,followed by nitration, bromination, cyclisation with 2-aminopyridine toform the 6-n-butanoylamido-3-(imidazo[1,2-a]pyridin-2-yl)-nitrobenzene,which is subsequently converted into the desired compound bycyclisation, after reduction of the nitro group, or

2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-1H-benzimidazole maybe obtained by nitration of methyl 3-methyl-4-n-butanoylamido-benzoate,subsequent reduction of the nitro group and cyclisation to yield2-n-propyl-4-methyl-6-methoxy-carbonyl-1H-benzimidazole, which is thenconverted into the desired compound using 2-methylamino-aniline withcyclisation.

A benzimidazole in which the alkoxy group is substituted in the 2-, 3-,4- or 5-position by an imidazole group may be obtained for example byreaction of a corresponding 7-hydroxy-benzimidazole, as described inEP-A-0 392 317, by reaction with a corresponding α, ω-dihaloalkane andsubsequent reaction with a corresponding imidazole.

A starting compound of general formula XXI or XXV is obtained byacylating a corresponding α-amino-acetone with a corresponding activatedbenzimidazole carboxylic acid, to obtain the desired α-amino-acetonefrom the corresponding α-amino acids according to Dakin/West (see Chem.Soc. Rev., 17, 91 (1988)).

A starting compound of general formula XXII is obtained by acylation ofa corresponding β-amino-alcohol and a compound of general formula XXIIIis obtained by cyclisation of a compound of general formula XXII thusobtained.

The acylated α-aminoketones mentioned above can also be converteddirectly into the corresponding substituted imidazoles by treatment withammonium acetate in glacial acetic acid analogously to Chem. Ber. 106,2415 (1973).

A starting compound of general formula XXVI is obtained by acylating acorresponding β-amino-alcohol with a corresponding activatedbenzimidazole carboxylic acid, the resulting compound subsequently beingcyclised and then reacted with a corresponding ethylenediamine.

The new compounds of general formula I and the physiologicallyacceptable salts thereof have valuable pharmacological properties. Theyare angiotensin antagonists, particularly angiotensin-II-antagonists.

By way of example, the following compounds were tested for theirbiological effects as described hereinafter:

A=4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

B=4'-[[2-n-butyl-7-[3-(benzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid trifluoroacetate,

C=4'-[[2-n-butyl-4-methyl-7-[4-(tetrahydro-benzimidazol-1-yl)-butoxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

D=4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

E=4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

F=4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

G=4'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

H=4'-[[2-n-butyl-6-(2,3-dimethylmaleic acidimino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acidsemihydrate,

I=4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl ]-biphenyl-2-carboxylic acid,

J=4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

K=4'-[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid semitrifluoroacetate,

L=4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

M=4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

N=4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

O=4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

P=4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

Q=4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

R=4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenylhydrochloride,

S=4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid,

T=4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl,

U=4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl,

V=4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

W=4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

X=4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

Y=4'-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

Z=4'-[(2-n-propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

AA=4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

BB=4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethylamino-propyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid-dihydrochloride-pentahydrate,

CC=4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

DD=4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

EE=4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl,

FF=4'-[[2-n-propyl-4-methyl-6-(1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid,

GG=4'-[[2-ethyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate,

HH=4'-[[2-n-propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate,

II=4'-[[2-ethyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate,

JJ=4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-di-trifluoroacetate,

KK=4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate,

LL=4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-l,5-dimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid×1.25 water,

MM=4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

NN=4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

OO=4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid,

PP=4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid and

QQ=4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,

Description of Method: Angiotensin II-receptor Bonding

The tissue (rats lung) is homogenised in Tris-buffer (50 mMol Tris, 150mMol NaCl, 5 mMol EDTA, pH 7.40) and centrifuged twice for 20 minutes at20,000×g. The finished pellets are resuspended in incubating buffer (50mMol Tris, 5 mMol MgCl₂, 0.2% BSA, pH 7.40) 1:75, based on the moistweight of the tissue. Each 0.1 ml of homogenate is incubated for 60minutes at 37° C. with 50 pM [¹²⁵ I]-antiotensin II (NEN, Dreieich, FRG)with increasing concentrations of the test substance in a total volumeof 0.25 ml. Incubation is ended by rapid filtration through glass fibrefilter mats. The filters are each washed with 4 ml of ice cold buffer(25 mMol Tris, 2.5 mMol MgCl₂, 0.1% BSA, pH 7.40). The boundradioactivity is measured using a gamma-counter. The corresponding IC₅₀value is obtained from the dose-activity curve.

In the test described, substances A to AM show the following IC₅₀values:

    ______________________________________                                        Substance     IC.sub.50 [nM]                                                  ______________________________________                                        A             510.0                                                           B             52.0                                                            C             130.0                                                           D             3.7                                                             E             14.0                                                            F             5.0                                                             G             1.2                                                             H             20.0                                                            I             6.6                                                             J             3.5                                                             K             17.0                                                            L             240.0                                                           M             12.0                                                            N             26.0                                                            O             3.4                                                             P             1.2                                                             Q             1.7                                                             R             20.0                                                            S             7.8                                                             V             1.2                                                             W             1.5                                                             X             40.0                                                            Y             10.0                                                            Z             15.0                                                            AA            3.4                                                             BB            1.3                                                             CC            12.0                                                            DD            3.8                                                             EE            2.6                                                             FF            6.0                                                             GG            46.0                                                            HH            38.0                                                            II            1.6                                                             JJ            37.0                                                            KK            3.2                                                             LL            19.5                                                            MM            7.4                                                             NN            0.9                                                             OO            1.7                                                             PP            1.3                                                             QQ            3.3                                                             ______________________________________                                    

Selected compounds were also investigated for their ability to lowerblood pressure using the following test protocol.

Description of Method: Renovascular Hypertension

Blood pressure lowering effects of angiotensin-II antagonists wereinvestigated in a rat model of renovascular hypertension. This model,the 2-kidney 1-clip rat, is characterized by an elevated renin activity(see J. Exper. Med. 59, 347-378 (1934), J. Applied Physiol. 31(1),142-144 (1971) and Gross D. R. in "Animal Models in CardiovascularResearch: Animal Models of hypertension" Martinus Nijhoff Publishers(1985)). The compounds are given two times daily by oral administrationto conscious freely moving rats which have been implanted with achronic-use pressure transmitter to monitor blood pressure and heartrate continuously (PhysioTel® telemetry device).

Male rats (140-150 g) are anaesthetized with pentobarbitone-sodium (50mg/kg i.p.). The abdominal cavity is opened by a midline incision. Asolid silver clip with an internal diameter of 0.20 mm is applied to theleft renal artery as close as possible to the aorta. The contralateralkidney is not disturbed. The catheter of a pressure transmitter(TA11PA-C40) is inserted in the abdominal aorta and the transmitterfixed to abdominal musculature. The abdomen is closed with sutures. Theanimals are allowed to recover for several weeks and housed individuallyin cages.

After the implantation of the chronic-use device, blood pressure andheart rate are transmitted by telemetry and the signals are received bya RA 1010 General Purpose Receiver (Data Science Int.). Data areacquired with the Dataquest® IV 1.11 System on a Hewlett Packard VectraES/12 386 computer.

Compounds are dissolved in 1M HCl or 1M NaOH. To stabilize the solutionβ-cyclodextrin (1.8 g/v %) is added. The solutions (0.3 and 1 mg/kg/2ml) are orally given by gavage at 10.00 a.m. and 4.00 p.m.

In the test described, substances D, E, T and U show the followingvalues:

    ______________________________________                                                    Dosage*  Blood pressure lowering                                  Substance   mg/kg    activity in mmHg                                         ______________________________________                                        D           0.3      -37                                                      D           1.0      -68                                                      E           0.3      -55                                                      E           1.0      -78                                                      T           0.3      -24                                                      U           1.0      -43                                                      ______________________________________                                         *two times daily                                                         

In addition, compounds D, E, F, G, H, M and O were tested on consciousrenally hypertensive rats for their effect after oral administrationusing methods known from the literature. At a dosage of 10 mg/kg thesecompounds exhibited a hypotensive effect.

Moreover, when the above-mentioned compounds described by options A andC were administered in a dose of 30 mg/kg i.v. no toxic side effects,e.g. negative inotropic effects or disorders in heart rhythm, wereobserved. The compounds are therefore well tolerated.

In view of their pharmacological properties, the new compounds and thephysiologically acceptable addition salts thereof are suitable for thetreatment of hypertension and cardiac insufficiency and also fortreating ischaemic peripheral circulatory disorders, myocardialischaemia (angina), for the prevention of the progression of cardiacinsufficiency after myocardial infarction and for treating diabeticnephropathy, glaucoma, gastrointestinal diseases and bladder diseases.

The new compounds and the physiologically acceptable addition saltsthereof are also suitable for treating pulmonary diseases, e.g. lungoedema and chronic bronchitis, for preventing arterial re-stenosis afterangioplasty, for preventing thickening of blood vessel walls aftervascular operations, and for preventing arteriosclerosis and diabeticangiopathy. In view of the effects of angiotensin on the release ofacetyl-choline and dopamine in the brain, the new angiotensinantagonists are also suitable for alleviating central nervous systemdisorders, e.g. depression, Alzheimer's disease, Parkinson syndrome,bulimia and disorders of cognitive function.

The dosage required for the compounds described by option A to achievethese effects in adults is appropriately, when administeredintravenously, 20 to 100 mg, preferably 30 to 70 mg, and, whenadministered orally, 50 to 200 mg, preferably 75 to 150 mg, 1 to 3 timesa day, and the dosage required for the compounds described by options Bto D to achieve these effects in adults is appropriately, whenadministered intravenously, 0.5 to 100 mg, preferably 1 to 70 mg, and,when administered orally, 0.1 to 200 mg, preferably 1 to 100 mg, 1 to 3times a day.

For this purpose, the compounds of general formula I prepared accordingto the invention, optionally in conjunction with other activesubstances, such as hypotensives, diuretics and/or calcium antagonists,may be incorporated together with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene-glycol, propylene-glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, in conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories.

Additional active substances which may be included in the combinationsmentioned above might be, for example, bendroflumethiazide,chlorothiazide, hydrochloro-thiazide, spironolactone, benzothiazide,cyclothiazide, ethacrinic acid, furosemide, metoprolol, prazosine,atenolol, propranolol, (di)hydralazine-hydrochloride, diltiazem,felodipin, nicardipin, nifedipin, nisoldipin and nitrendipin. The dosagefor these active substances is appropriately one fifth of the lowestrecommended dose up to 1/1 of the normally recommended dose, i.e., forexample, 15 to 200 mg of hydrochlorothiazide, 125 to 2000 mg ofchlorothiazide, 15 to 200 mg of ethacrinic acid, 5 to 80 mg offurosemide, 20 to 480 mg of propranolol, 5 to 60 mg of felodipine, 5 to60 mg of nifedipin or 5 to 60 mg of nitrendipin.

The Examples which follow are intended to illustrate the invention:

EXAMPLE 14'-[[2-n-Butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid Hydrate

0.7 g (1.15 mMol) of tert.-butyl4'-[[2-n-butyl-7-[5-(imidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateare dissolved in 35 ml of methylene chloride, 5 ml of trifluoroaceticacid are added and the mixture is stirred for 12 hours at ambienttemperature. It is diluted with methylene chloride and extracted withwater and with saturated sodium bicarbonate solution. The organic phaseis dried over sodium sulphate and evaporated down in vacuo. The crudeproduct thus obtained is purified over a silica gel column (particlesize: 0.063-0.02 mm, ethyl acetate/ethanol/ammonia--90:10:0.1) andcrystallised from acetone.

Yield: 0.19 g (29.9% of theory),

Melting point: 185°-187° C.

C₃₄ H₃₈ N₄ O₃ ×H₂ O (550.70)

Calculated: C 71.81 H 7.09 N 9.85

Found: 72.03 7.19 9.71

Mass spectrum: m/e=M⁺ 550

The following compounds are obtained analogously to Example 1:

4'-[[2-n-butyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-ethyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-4-methyl-6-(phenylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-ethyl-4-methyl-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(n-butylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(benzylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-n-butylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-benzylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(n-hexylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-ethylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(piperidinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 24'-[[2-n-Butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 69.4% of theory,

Melting point: 208°-210° C.

C₃₂ H₃₄ N₄ O₃ (522.64)

Calculated: C 73.54 H 6.56 N 10.72

Found: 73.45 6.62 10.60

R_(f) value: 0.50 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5)

EXAMPLE 34"-[[2-n-Butyl-7-[3-(benzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid Trifluoroacetate

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[3-(benzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 87.8% of theory,

Melting point: 221°-223° C.

C₃₆ H₃₆ N₄ O₃ ×CF₃ COOH (686.72)

Calculated: C 66.46 H 5.43 N 8.15

Found: 66.58 5.62 8.31

R_(f) value: 0.45 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5

EXAMPLE 44'-[[2-n-Butyl-7-[4-(imidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid Hydrate

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[4-(imidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 68.5% of theory,

Melting point: 126°-128° C.

C₃₃ H₃₆ N₄ O₃ ×H₂ O (554.68)

Calculated: C 71.46 H 6.91 N 10.10

Found: 71.63 7.02 9.98

Mass spectrum: m/e=536

EXAMPLE 54'-[[2-n-Butyl-7-[2-(benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[2-(benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 78.1% of theory,

Melting point: 167°-169° C.

C₃₅ H₃₄ N₄ O₃ (558.68)

Calculated: C 75.25 H 6.13 N 10.03

Found: 75.03 6.17 9.95

EXAMPLE 64'-[[2-n-Butyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 74'-[[2-n-Butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 84'-[[2-n-Butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-1-yl)butyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-4-methyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 86% of theory

Melting point: 229°-231° C.

C₃₇ H₄₂ N₄ O₃ (590.76)

Calculated: C 75.23 H 7.17 N 9.48

Found: 75.34 7.06 9.38

EXAMPLE 94'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in dimethylformamide.

Yield: 63.9% of theory,

Melting point: 261°-263° C.

C₃₃ H₃₀ N₄ O₂ (514.60)

Calculated: C 77.02 H 5.87 N 10.89

Found: 76.90 5.85 10.99

The following compounds are obtained analogously to Example 9:

4'-[[2-n-propyl-4-methyl-6-(1-n-propylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl ]-biphenyl-2-carboxylic acid

4'-[[2-n-propyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 104'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chlorideare added to a solution of 1.60 g (3.3 mMol) of4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenylin 50 ml of dimethylformamide and the mixture is stirred for 24 hours at140° C. Then water is added and the precipitate is removed by suctionfiltering. The crude product thus obtained is purified by chromatographyover silica gel (300 g of silica gel, methylene chloride+6% ethanol).

Yield: 900 mg (51% of theory),

Melting point: 228°-230° C.

C₃₃ H₃₀ N₈ (538.70)

Calculated: C 73.58 H 5.61 N 20.80

Found: 73.48 5.55 20.70

The following compounds are obtained analogously to Example 10:

4'-[[2-n-propyl-4-methyl-6-(1-n-hexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(1-cyclobutylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(1-cyclohexylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-7-[2-(imidazol-1-yl)-ethoxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-7-[4-(imidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-7-[5-(imidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-7-[2-(benzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-7-[3-(benzimidazol-1-yl)-propyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-7-[4-(benzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-7-[5-(benzimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-7-[2-(4,5,6,7-tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-7-[4-(tetrahydrobenzimidazol-1-yl)-butyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)pentyloxy]-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(phenylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-ethyl-4-methyl-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-propyl-4-methyl-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(n-pentylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(n-butylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(benzylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(allylaminocarbonylamino)-benzimidazol-1-yl]-methyl ]-2-(1H-tetrazol-5-yl ) -biphenyl

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylmethylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-n-butylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(methylaminocarbonyl-benzylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(n-hexylaminocarbonyl-cyclohexylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(cyclohexylaminocarbonyl-ethylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(dimethylaminocarbonyl-n-pentylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(pyrrolidinocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(piperidinocarbonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 114'-[(2-n-propyl-4-methyl-6-phthalimino-benzimidazol-1-yl)methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-phthalimino-benzimidazol-1-yl)-methyl]-2-cyanobiphenyland sodium azide in dimethylformamide.

Yield: 6.8% of theory,

Melting point: sintering from 160° C.

C₃₃ H₂₇ N₇ O₂ (553.60)

Calculated: C 71.59 H 4.92 N 17.71

Found: 71.39 4.88 17.54

EXAMPLE 124'-[(2-n-Butyl-4-methyl-6-phthalimino-benzimidazol-1-yl)methyl]-2-(1H-tetrazol,5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-butyl-4-methyl-6-phthalimino-benzimidazol-1-yl)-methyl]-2-cyanobiphenyland sodium azide in dimethylformamide.

Yield: 7.1% of theory,

Melting point: sintering from 150° C.

C₃₄ H₂₉ N₇ O₂ (567.70)

Calculated: C 71.94 H 5.15 N 17.27

Found: 71.75 5.19 17.22

EXAMPLE 134-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 25.0% of theory,

Melting point: sintering from 170° C.

C₃₃ H₂₉ N₇ O (539.60)

Calculated: C 73.45 H 5.42 N 18.17

Found: 73.20 5.41 18.33

EXAMPLE 144'-[[2-n-Butyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 21.0% of theory,

Melting point: sintering from 165° C.

C₃₄ H₃₁ N₇ O (553.70)

Calculated: C 73.76 H 5.64 N 17.71

Found: 73.58 5.33 17.4

EXAMPLE 154'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 49.0% of theory,

Melting point: Sintering from 186° C.

C₂₉ H₃₁ N₇ O₂ S (541.70)

Calculated: C 64.30 H 5.77 N 18.10 S 5.92

Found: 64.10 5.39 18.01 5.98

EXAMPLE 164'-[[2-Ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 60.0% of theory,

Melting point: amorphous, sintering from 194° C.

C₂₈ H₂₉ N₇ O₂ S (527.70)

Calculated: C 63.74 H 5.54 N 18.58 S 6.08

Found: 63.83 5.66 18.41 5.82

EXAMPLE 174'-[[2-n-Butyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethyl-formamide.

Yield: 48.0% of theory,

Melting point: amorphous, sintering from 183° C.

C₃₀ H₃₃ N₇ O₂ S (555.70)

Calculated: C 64.84 H 5.99 N 17.64 S 5.77

Found: 64.53 5.66 17.63 5.55

EXAMPLE 184'-[[2-n-propyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 27.0% of theory,

Melting point: amorphous, sintering from 189° C.

C₃₀ H₃₃ N₇ O₂ S (555.70)

Calculated: C 64.84 H 5.99 N 17.64 S 5.77

Found: 64.81 5.68 17.87 5.31

EXAMPLE 194'-[[2-Ethyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-ethyl-4-ethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 39.0% of theory,

Melting point: amorphous, sintering from 212° C.

C₂₉ H₃₁ N₇ O₂ S (541.70)

Calculated: C 64.30 H 5.77 N 18.10 S 5.92

Found: 64.30 5.51 17.99 5.59

EXAMPLE 204-[[2-n-propyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethyl-formamide.

Yield: 22.0% of theory,

Melting point: amorphous

C₃₁ H₃₅ N₇ O₂ S (569.70)

Calculated: C 65.35 H 6.19 N 17.21 S 5.63

Found: 65.13 6.10 17.54 5.40

EXAMPLE 214-[[2-Ethyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-ethyl-4-isopropyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethyl-formamide.

Yield: 24.0% of theory,

Melting point: amorphous, sintering from 209° C.

C₃₀ H₃₃ N₇ O₂ S (555.70)

Calculated: C 64.84 H 5.99 N 17.64 S 5.77

Found: 64.99 5.71 17.43 5.71

EXAMPLE 224'-[[2-n-propyl-4-trifluoromethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-trifluoromethyl-6-(butanesultam-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 17.0% of theory,

Melting point: 199°-203° C.

C₂₉ H₂₈ F₃ N₇ O₂ S (595.70)

Calculated: C 58.48 H 4.74 N 16.46

Found: 58.28 4.43 16.22

EXAMPLE 234'-[[2-n-propyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 42.0% of theory,

Melting point: 161°-163° C.

C₃₂ H₃₁ N₇ O₂ S (577.70)

Calculated: C 66.53 H 5.41 N 16.97 S 5.55

Found: 66.32 5.36 16.70 5.31

EXAMPLE 244'-[[2-n-Butyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-l]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 37.0% of theory,

Melting point: 150°-153° C.

C₃₃ H₃₃ N₇ O₂ S (591.70)

Calculated: C 66.98 H 5.62 N 16.57

Found: 66.71 5.38 16.39

The following compounds are obtained analogously to Example 24:

4'-[[2-ethyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-ethyl-4-methyl-6-(3-benzyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 254'-[[2-n-Butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 48.0% of theory,

Melting point: 233°-235° C.

C₃₄ H₃₂ N₄ O₂ (528.70)

Calculated: C 77.25 H 6.10 N 10.60

Found: 77.10 5.98 10.46

EXAMPLE 264'-[[2-n-Butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 41.0% of theory,

Melting point: 235°-237° C.

C₃₄ H₃₂ N₈ (552.70)

Calculated: C 73.89 H 5.84 N 20.28

Found: 73.67 5.81 19.93

The following compounds are obtained analogously to Example 26:

4'-[[2-n-butyl-4-methyl-6-(1-ethylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(1-cyclopropylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(1-n-pentylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(1-cyclopentylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 274'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethyl-formamide.

Yield: 51.0% of theory,

Melting point: amorphous, from 140° C. (sintering)

C₃₀ H₃₁ N₇ O (505.60)

Calculated: C 71.26 H 6.18 N 19.39

Found: 71.08 6.22 19.47

EXAMPLE 284'-[[2-n-Butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethyl-formamide.

Yield: 39.0% of theory,

Melting point: amorphous, from 128° C. (sintering)

C₃₁ H₃₃ N₇ O (519.70)

Calculated: C 71.65 H 6.40 N 18.87

Found: 71.44 6.23 18.59

EXAMPLE 294'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared from4'-[[2-n-propyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)biphenylby cleaving the triphenylmethyl group with methanolic hydrochloric acid.

Yield: 51.0% of theory,

Melting point: amorphous, sintering from 115° C.

C₃₀ H₃₁ N₇ O (505.60)

Calculated: C 71.26 H 6.18 N 19.39

Found: 71.51 6.39 19.09

EXAMPLE 304'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 54.0% of theory,

Melting point: 202°-204° C.

C₃₁ H₂₆ N₄ O₂ (486.60)

Calculated: C 76.52 H 5.39 N 11.52

Found: 76.33 5.32 11.30

The following compounds may be prepared analogously to Example 30:

4'-[[2-n-propyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-6-(6-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(6-aminocarbonyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-6-(6-chloro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-6-(2,3-dimethyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 314'-[[2-n-Butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicAcid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 41.0% of theory,

Melting point: 193°-195° C.

C₃₂ H₂₈ N₄ O₂ (500.60)

Calculated: C 76.78 H 5.64 N 11.19

Found: 76.73 5.48 11.00

EXAMPLE 324'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 28.0% of theory,

Melting point: 187°-189° C.

C₃₁ H₂₆ N₈ (510.60)

Calculated: C 72.92 H 5.13 N 21.95

Found: 72.80 4.97 21.74

The following compounds may be prepared analogously to Example 32:

4'-[[2-n-propyl-6-(7-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(5-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-6-(6-bromo-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4-'[[2-n-propyl-6-(5,7-dimethyl-imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-6-(3-methyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(2-phenyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 334'-[[2-n-Butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 23.0% of theory,

Melting point: 170°-173° C.

C₃₂ H₂₈ N₈ (524.60)

Calculated: C 73.26 H 5.38 N 21.36

Found: 73.09 5.32 21.20

EXAMPLE 344'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 38.0% of theory, Melting point: 195°-197° C. (after evaporationand without recrystallisation) Melting point: 299°-303° C. (methylenechloride/ethanol=20:1) C₃₂ H₂₈ N₄ O₂ (500.60) Calculated: C 76.78 H 5.64N 11.19 Found: 76.55 5.61 10.87

The following compounds may be prepared analogously to Example 34:

4'-[[2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-4-methyl-6-(7-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-4-methyl-6-(6-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(5-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(5,7-dimethyl-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-ethyl-4-methyl-6-(6-aminocarbonyl-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-ethyl-4-methyl-6-(6-chloro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 354'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 21.0% of theory, Melting point: sintering from 181° C. C₃₂ H₂₈ N₈(524.60) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.10 5.24 21.13

The following compounds may be prepared analogously to Example 35:

4'-[[2-n-propyl-4-methyl-6-(5-methyl-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 364'-[[2-n-Butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 51.0% of theory, Melting point: 194°-197° C. C₃₃ H₃₀ N₄ O₂(514.60) Calculated: C 77.02 H 5.88 N 10.89 Found: 76.81 5.78 10.64

The following compounds are obtained analogously to Example 36:

4'-[[2-n-propyl-6-(pyrrolidin-2-on-5-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(pyrrolidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 374'-[[2-n-Butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 26.0% of theory, C₃₃ H₃₀ N₈ (538.60) Calculated: C 73.58 H 5.61 N20.80 Found: 73.39 5.40 20.92

The following compounds are obtained analogously to Example 37:

4'-[[2-n-propyl-6-(pyrrolidin-2-on-5-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(pyrrolidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(piperidin-2-on-6-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-6-(piperidin-2-on-6-yl)-benzimidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(piperidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-6-(piperidin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-ethyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-6-(pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl4'-[[2-n-butyl-6-(quinolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-ethyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 384'-[[2-n-Butyl-4-methyl-6-(2,2-dimethylpropionylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-4-methyl-6-(2,2-dimethylpropionylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 394'-[[2-n-Butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[2-(tetrahydrobenzimidazol-1-yl)-ethoxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 81% of theory, Melting point: 236°-237° C. C₃₅ H₃₈ N₄ O₃ (562.71)Calculated: C 74.71 H 6.81 N 9.96 Found: 74.51 6.79 9.98

EXAMPLE 404'-[[2-n-Butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)pentyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-4-methyl-7-[5-(tetrahydrobenzimidazol-1-yl)-pentyloxy]-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 414'-[[2-n-Butyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-butyl-7-[3-(tetrahydrobenzimidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 424'-[[2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 47% of theory, Melting point: 224°-226° C. (after evaporation andwithout recrystallisation) Melting point: 294°-297° C. (methylenechloride/ethanol=20:1) C₃₁ H₂₇ N₅ O₂ (501.60) Calculated: C 74.23 H 5.43N 13.96 Found: 74.10 5.31 13.66

EXAMPLE 434'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 43% of theory, Melting point: 192°-195° C. (after evaporation andwithout recrystallisation) Melting point: >300° C. (methylenechloride/ethanol-20:1) C₃₀ H₂₆ N₄ O₂ S (506.64) Calculated: C 71.12 H5.17 N 11.06 S 6.33 Found: 70.97 5.19 10.88 6.09

The following compounds may be prepared analogously to Example 43:

4'-[[2-n-propyl-4-methyl-6-(3-methyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(2,3-dimethyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-4-methyl-6-(2,3-trimethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-{[2-n-propyl-4-methyl-6-(2,3-tetramethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-ethyl-4-methyl-6-(2-phenyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 444'-[[2-n-Propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 21% of theory, Melting point: amorphous, sintering from 196° C.C₃₀ H₂₆ N₈ S (530.67) Calculated: C 67.90 H 4.94 N 21.12 S 6.04 Found:67.77 4.84 21.00 5.87

The following compounds may be prepared analogously to Example 44:

4'-[[2-n-propyl-4-methyl-6-(3-methyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(2,3-dimethyl-imidazo[2,1-b]thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(2,3-trimethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-ethyl-4-methyl-6-(2,3-tetramethylene-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(2-phenyl-imidazo[2,1-b]-thiazol-6-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 454'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethyl-formamide.

Yield: 28% of theory, Melting point: 202°-205° C. C₃₂ H₂₈ N₈ (524.64)Calculated: C 73.26 H 5.38 N 21.36 Found: 73.01 5.22 21.56

The following compounds are obtained analogously to Example 45:

4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

40'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 464'-[[2-n-Propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.-butyl4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 43% of theory, Melting point: 239°-242° C. C₃₂ H₂₈ N₄ O₂ (500.61)Calculated: C 76.78 H 5.64 N 11.19 Found: 76.55 5.60 11.41

The following compounds are obtained analogously to Example 46:

4'-[[2-ethyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-butyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(1-n-hexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(1-cyclopropyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

4'-[[2-n-propyl-4-methyl-6-(1-cyclohexyl-benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 474'-[[2-n-Butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared from4'-[[2-n-butyl-7-[3-(imidazol-1-yl)-propyloxy]-4-methyl-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenylby cleaving the 1-triphenylmethyl group by means ofethanol/hydro-chloric acid.

Yield: 89.8% of theory, Melting point: 83°-87° C. C₃₂ H₃₄ N₈ O×1.5 H₂ O(573.69) Calculated: C 66.99 H 6.50 N 19.53 Found: 66.83 6.52 19.43

EXAMPLE 484'-[[6-(N-Benzenesulphonyl-methylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[[6-(N-benzenesulphonylmethylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 95.6% of theory, Melting point: 211°-212° C. C₃₃ H₃₃ N₃ O₄ S(567.70) Calculated: C 69.80 H 5.86 N 7.40 S 5.65 Found: 69.52 5.92 7.335.84

EXAMPLE 494'-[[6-(N-Benzenesulphonyl-n-pentylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[[6-(N-benzenesulphonyl-n-pentylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 81.8% of theory, Melting point: 232°-233° C. C₃₇ H₄₁ N₃ O₄ S(623.81) Calculated: C 71.24 H 6.62 N 6.74 S 5.14 Found: 71.30 6.77 6.685.33

EXAMPLE 504'-[[2-n-Butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[[2-n-butyl-6-(isopropylcarbonylamino)-4-methyl-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 86.3% of theory, Melting point: 313°-315° C. C₃₀ H₃₃ N₃ O₃(483.61) Calculated: C 74.51 H 6.88 N 8.69 Found: 74.37 7.10 8.74

EXAMPLE 51 4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acidimino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

Prepared analogously to Example 1 from tert.butyl4'-[[2-n-butyl-6-(2,3-dimethylmaleic acidimino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate andtrifluoroacetic acid in methylene chloride.

Yield: 88.9% of theory, Melting point: 321°-322° C. C₃₂ H₃₁ N₃ O₄ ×0.5H₂ O (530.62) Calculated: C 72.43 H 6.08 N 7.92 Found: 72.89 6.16 7.89

EXAMPLE 52 4'-[[6-(2,3-Dimethylmaleic acidimino)-2-n-propyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid semihydrate

Prepared analogously to Example 1 from tert.butyl4'-[[6-(2,3-dimethylmaleic acidimino)-2-n-propyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 75.4% of theory, Melting point: 329°-331° C. C₃₁ H₂₉ N₃ O₄ ×0.5H₂ O (516.60) Calculated: C 72.08 H 5.85 N 8.13 Found: 72.04 5.84 7.96

EXAMPLE 534'-[(6-Acetamino-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid trifluoroacetate semihydrate

Prepared analogously to Example 1 from tert.butyl4'-[(6-acetamino-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 95.7% of theory, Melting point: 112°-114° C. (amorphous) C₂₈ H₂₉N₃ O₃ ×CF₃ COOH×0.5 H₂ O (578.59) Calculated: C 62.28 H 5.40 N 7.26Found: 62.57 5.46 7.21

EXAMPLE 544'-[[2-n-Butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[[2-n-butyl-4-methyl-6-(morpholinocarbonylamino)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 80.9% of theory, Melting point: 279°-281° C. C₃₁ H₃₄ N₄ O₄(526.64) Calculated: C 70.70 H 6.51 N 10.64 Found: 70.48 6.50 10.51

EXAMPLE 554'-[[2-n-Butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid semitrifluoroacetate

Prepared analogously to Example 1 from tert.butyl4'-[[2-n-butyl-6-(cyclohexylaminocarbonylamino)-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 76.9% of theory, Melting point: 288°-289° C. C₃₃ H₃₈ N₄ O₃ ×0.5CF₃ COOH (595.70) Calculated: C 68.55 H 6.51 N 9.41 Found: 69.08 7.029.65

EXAMPLE 564'-[[2-n-Propyl-4-isopropyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[[2-n-propyl-4-isopropyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 14% of theory, Melting point: amorphous C₃₅ H₃₃ N₇ O (567.71)Calculated: C 74.05 H 5.86 N 17.27 Found: 73.97 5.82 17.26 Massspectrum: M⁺ =567

EXAMPLE 574'-[[2-n-Propyl-5-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[[2-n-propyl-5-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 32% of theory, Melting point: 250°-253° C. C₃₁ H₂₆ N₄ O₂ (486.60)Calculated: C 76.52 H 5.39 N 11.52 Found: 76.28 5.47 11.27

EXAMPLE 584'-[(2-n-Propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 64% of theory, Melting point: 217°-219° C. C₃₄ H₃₂ N₄ O₂ (528.70)Calculated: C 77.24 H 6.10 N 10.60 Found: 77.12 6.09 10.75

EXAMPLE 594'-[(2-n-Propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 15% of theory, Melting point: 215°-217° C. C₃₄ H₃₂ N₈ (552.70)Calculated: C 73.89 H 5.84 N 20.28 Found: 73.66 6.02 20.56

EXAMPLE 604'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 52% of theory, Melting point: 244°-246° C. C₃₃ H₂₈ N₄ O₂ (512.60)Calculated: C 77.32 H 5.51 N 10.93 Found: 77.75 5.71 10.94

EXAMPLE 614'-[(2-Cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-cyclopropyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 59% of theory, Melting point: 245°-247° C. C₃₃ H₂₈ N₈ (536.65)Calculated: C 73.86 H 5.26 N 20.88 Found: 73.95 5.42 20.90

EXAMPLE 624'-[(2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 63% of theory, Melting point: 189°-191° C. C₃₄ H₃₀ N₄ O₂ (526.60)Calculated: C 77.55 H 5.74 N 10.64 Found: 77.35 5.92 10.40

EXAMPLE 634'-[(2-Cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 61% of theory, Melting point: 197°-199° C. C₃₄ H₃₀ N₈ (550.70)Calculated: C 74.16 H 5.49 N 20.35 Found: 74.12 5.74 20.67

EXAMPLE 644'-[(2-n-Propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-y)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 34% of theory, Melting point: 250°-252° C. C₃₃ H₂₉ FN₄ O₂(532.60) Calculated: C 74.42 H 5.49 N 10.52 Found: 74.14 5.64 10.54

The following compounds are obtained analogously to Example 64:

4'-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(isoquinolin-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 654'-[(2-n-Propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyrimidin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 16.5% of theory, Melting point: from 275° C. (decomp.) C₃₁ H₂₇ N₉×H₂ O (543.65) Calculated: C 68.49 H 5.38 N 23.19 Found: 68.25 5.5023.37

The following compounds are obtained analogously to Example 65:

4'-[(2-n-propyl-4-methyl-6-(pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[(2-n-propyl-4-methyl-6-(quinolin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[(2-n-propyl-4-methyl-6-(isoquinolin-3-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[(2-n-propyl-4-methyl-6-(isoquinolin-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 664'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 67% of theory, Melting point: from 240° C. (sinters) C₃₂ H₃₂ N₄O₂ (504.64) Calculated: C 76.16 H 6.39 N 11.10 Found: 75.94 6.46 11.20

The following compounds are obtained analogously to Example 66:

4'-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 674'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 73.5% of theory, Melting point: from 275° C. (decomp.) C₃₂ H₃₂ N₈(528.67) Calculated: C 72.70 H 6.10 N 21.20 Found: 72.40 6.07 21.48

The following compounds are obtained analogously to Example 67:

4'-[(2-n-butyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 684'-[(2-n-Propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-methyl-6-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 76% of theory, Melting point: 243°-245° C. C₃₃ H₂₉ FN₄ O₂(532.60) Calculated: 74.42 H 5.49 N 10.52 Found: 74.74 5.52 10.77 Massspectrum: m/e=532

EXAMPLE 694'-[(2-n-Propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl-]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 7.5% of theory, Melting point: 209°-210° C. C₃₂ H₂₆ C₁ N₃ O₃(536.04) Mass spectrum: m/e=535/537 R_(f) value: 0.25 (silica gel;methylene chloride/ethanol=9:1)

EXAMPLE 704'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 52.7% of theory, Melting point: 292°-295° C. C₃₂ H₂₇ CN₄ O₂(535.06) R_(f) value: 0.30 (silica gel; methylene chloride/ethanol=19:1)Calculated: C 71.90 H 5.08 N 10.45 Cl 6.63 Found: 71.29 5.21 10.40 6.76

EXAMPLE 714'-[(2-n-Propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenylhydrochloride

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-chloro-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 54.8% of theory, Melting point: sintering from 204° C. C₃₂ H₂₇ C₁N₈ ×HCl (595.55) R_(f) value: 0.20 (silica gel; petroleum ether/ethylacetate=1:1 and 1% glacial acetic acid) Calculated: C 62.55 H 4.71 N18.85 Cl 11.85 Found: 62.34 4.97 18.84 11.57

EXAMPLE 724'-[(2-n-Propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-chloro-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 24.6% of theory, Melting point: 246°-248° C. C₃₂ H₂₆ ClN₇ O(560.08) R_(f) value: 0.15 (silica gel; methylene chloride/ethanol=9:1)Calculated: C 69.00 H 4.67 N 17.55 Cl 6.40 Found: 68.26 4.75 17.73 6.97

The following compound is obtained analogously to Example 72:

4'-[(2-n-propyl-4-methyl-6-(4-methyl-imidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 734'-[(2-n-Propyl-4-chloro-6-(cyclohexylaminocarbonyl-amino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-chloro-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 75% of theory, Melting point: 222°-224° C. C₃₁ H₃₃ ClN₄ O₃(545.09) R_(f) value: 0.15 (silica gel; methylene chloride/ethanol=19:1)Calculated: C 68.50 H 6.10 N 10.30 Cl 6.48 Found: 68.89 5.98 10.02 7.04

EXAMPLE 744'-[(2-n-Propyl-4-methyl-6-amidino-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid hydrate

a) Methyl4'-[(2-n-propyl-4-methyl-6-amidino-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate

2.1 g (5 mMol) of methyl4'-[(2-n-propyl-4-methyl-6-cyano-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateare dissolved in 250 ml of methanol at ambient temperature withstirring. Hydrogen chloride is introduced at 10°-20° C. for 3 hourswhilst cooling with ice. The mixture is then stirred for a further 3hours at ambient temperature. The solvent is distilled off in vacuo, theresidue is twice mixed with ether and concentrated by evaporation. Theiminoether formed is taken up in 250 ml of methanol and mixed with 10.0g of ammonium carbonate. The reaction mixture is stirred for 12 hours atambient temperature. After the solvent has been removed vacuo theresidue is purified over a silica gel column (particle size 0.063-0.032mm), using as eluant mixtures of methylene chloride and methanol ofincreasing polarity (9:1 and 8:2). The uniform fractions are evaporateddown in vacuo.

Yield: 1.5 g (58% of theory) R_(f) value: 0.15 (silica gel; eluant:methylene chloride/methanol=9:1)

b)4'-[(2-n-Propyl-4-methyl-6-amidino-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

0.51 g (1.0 mMol) of methyl4'-[(2-n-propyl-4-methyl-6-amidino-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateare dissolved in 6 ml of tetrahydrofuran, 2.8 ml of 1.4M aqueous lithiumhydroxide solution and 3 ml of water are added and the mixture isstirred for 2 days at ambient temperature. Then a solution of 300 mg ofammonium chloride in 4 ml of water is added. The mixture is stirred for5 minutes, the precipitate formed is suction filtered, washed withacetone and dried over potassium hydroxide.

Yield: 0.25 g (59% of theory), Melting point: 270°-271° C. (decomp.) C₂₆H₂₆ N₄ O₂ ×H₂ O (426.53) Calculated: C 70.25 H 6.35 N 12.60 Found: 70.046.23 12.50 R_(f) value: 0.55 (silica gel; eluant: methylenechloride/methanol/ammonia=2:1:0.25)

The following compound is obtained analogously to Example 74:

4'-[(2-n-propyl-4-methyl-6-(3-methyl-imidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 754'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

a) 3-Methyl-4-butyrylamino-5-nitro-acetophenone

32.6 g (148 mmol) of 3-methyl-4-butyrylamino-acetophenone are added inbatches at -15° C. to 300 ml of fuming nitric acid with stirring, andstirred for a further 30 minutes at -15° C. The reaction mixture is thenpoured onto 3 liters of ice, with stirring, the crude productprecipitated is suction filtered, washed with 400 ml of water, dried andpurified by recrystallisation from ethanol/diethylether (1:1).

Yield: 23.8 g (61.0% of theory), R_(f) value: 0.32 (silica gel;methylene chloride), R_(f) value: 0.48 (silica gel; methylenechloride/methanol=50:1).

b) 3-Methyl-4-butyrylamino-5-nitro-1-bromoacetophenone

A solution of 16.0 g (200 mmol) of bromine in 140 ml of dioxane is addeddropwise to a solution of 23.8 g (90 mmol) of3-methyl-4-butyrylamino-5-nitro-acetophenone in 900 ml ofdichloromethane at ambient temperature, with stirring, so slowly thattotal decolorisation of the reaction mixture occurs constantly. Themixture is then stirred for a further two hours, then the reactionmixture is evaporated to dryness in vacuo, the residue obtained istriturated with about 20 ml of dichloromethane/diethylether (1:1),suction filtered and then dried. 23 g (74% of theory) of3-methyl-4-butyrylamino-5-nitro-ω-bromoacetophenone are thus obtained,still containing about 10% starting material. The product is furtherreacted without any more purification. R_(f) value: 0.69 (silica gel;methylene chloride/methanol=50:1) R_(f) value: 0.84 (silica gel;methylene chloride/methanol=9:1).

c) 2-Butyrylamino-3-nitro-5-(imidazo-4-yl)-toluene

A solution of 6.8 g (20 mmol) of3-methyl-4-butyrylamino-5-nitro-ω-bromoacetophenone in 20 ml offormamide is heated to 140° C. for two hours. The cooled solution isthen poured into about 50 ml of 1N ammonia and stirred for about 15minutes. The crude product precipitated is suction filtered, washed withabout 50 ml of water and dried. In this way, 4.4 g (75% of theory) ofthe product are obtained, which is further reacted without any morepurification. R_(f) value: 0.29 (silica gel; methylenechloride/methanol=9:1)

d) 2-Butyrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene

1.3 g (9.5 mmol) of methyliodide are added dropwise at ambienttemperature to a solution of 2.5 g (8.7 mmol) of2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2 g (30 mmol) ofpotassium carbonate dihydrate in 30 ml of dimethylsulfoxide and themixture is then stirred for two hours. The reaction mixture is thenstirred into about 150 ml of water and extracted four times with 25 mlof ethylacetate. The organic extracts are washed with about 30 ml ofwater, dried and evaporated down. The crude product thus obtained ispurified by column chromatography (300 g of silica gel, eluant:methylene chloride/methanol=30:1).

Yield: 640 mg (24% of theory), R_(f) value: 0.54 (silica gel; methylenechloride/methanol=9:1)

e) 2-Butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene

640 mg (2.1 mmol) of2-butyrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene arehydrogenated in 30 ml of methanol after the addition of about 200 mg ofpalladium/charcoal (20%) at ambient temperature under a hydrogenpressure of 5 bar. After all the hydrogen has been absorbed the catalystis removed by filtering and the filtrate is evaporated down. The crudeproduct obtained is further reacted without any more purification.

Yield: 600 mg (100% of theory), R_(f) value: 0.23 (silica gel; methylenechloride/methanol=9:1)

f) 2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole

600 mg (2.1 mmol) of2-butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene are refluxedfor one hour in 10 ml of glacial acetic acid. Then the mixture isevaporated to dryness in vacuo, the residue is mixed with about 15 ml ofwater, made alkaline with ammonia and extracted four times with about 10ml of ethylacetate. The organic extracts are washed with about 15 ml ofwater, dried and finally evaporated down. The crude product thusobtained is further reacted without any more purification.

Yield: 420 mg (79% of theory), R_(f) value: 0.37 (silica gel; methylenechloride/methanol=9:1)

g)Tert-butyl-4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-carboxylate

280 mg (0.8 mmol) of tert.butyl-4'-bromomethyl-biphenyl-2-carboxylateare added to a solution of 200 mg (0.79 mmol) of2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg(0.8 mmol) of potassium tert.butoxide in 5 ml of dimethylsulfoxide andthe mixture is stirred for 90 minutes at ambient temperature, thenstirred into about 40 ml of water, extracted four times with about 10 mlof ethylacetate, then the organic extracts are washed with 10 ml ofwater, dried and evaporated to dryness. The crude product thus obtainedis purified by column chromatography (100 g silica gel, eluant:dichloromethane/methanol=30:1).

Yield: 230 mg (56% of theory), R_(f) value: 0.61 (silica gel; methylenechloride/methanol=9:1)

h)4'-[2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

A solution of 230 mg (0.44 mmol) oftert.butyl-4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand 2 ml of trifluoroacetic acid in 10 ml of dichloromethane was stirredovernight at ambient temperature and then evaporated to dryness. Theresidue was dissolved in about 5 ml of dilute sodium hydroxide solution,the solution was neutralised with acetic acid, the precipitate wassuction filtered, washed with water and dried.

Yield: 120 mg (59% of theory); Melting point: 293°-295° C. R_(f) value:0.39 (silica gel; methylene chloride/methanol=9:1)

The following compounds are obtained analogously to Example 75:

4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-cyclohexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 764'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 24% of theory Melting point: 255°-257° C. R_(f) -value: 0.24(silica gel; methylene chloride/methanol=9:1) C₂₉ H₂₈ N₈ ×H₂ O (506.62)calculated: C 68.75 H 5.97 N 22.12 found: 68.90 5.97 22.03

The following compounds are obtained analogously to Example 76:

4'-[(2-n-propyl-4-methyl-6-(1-ethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

4'-[(2-n-propyl-4-methyl-6-(1-cyclohexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

EXAMPLE 774'-[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 21% of theory Melting point: amorph. R_(f) -value: 0.27 (silicagel; methylene chloride/ethanol=9:1) C₃₁ H₃₀ N₈ (514.64) calculated: C72.35 H 5.88 N 21.78 found: 72.01 5.82 21.44

EXAMPLE 784'-[(2-n-Propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(8-methyl-imidazo-[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 87% of theory Melting point: 295°-297° C. R_(f) -value: 0.34(silica gel; methylene chloride/ethanol=9:1) C₃₃ H₃₀ N₄ O₂ ×H₂ O(532.65) calculated: C 74.41 H 6.06 N 10.52 found: 74.81 6.05 10.43

EXAMPLE 794'-[(2-n-Propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(2-pyridyl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 56% of theory, Melting point: from 136° C. (decomp.) C₃₀ H₂₇ N₇×0.5 H₂ O (494.60) Calculated: C 72.85 H 5.71 N 19.83 Found: 72.45 6.0119.83

EXAMPLE 804'-[(2-n-Propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(8-methyl-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 19% of theory Melting point: amorph. R_(f) -value: 0.36 (silicagel; methylene chloride/ethanol=9:1) C₂₉ H₂₈ N₈ ×H₂ O (538.61) massspectrum: m/e=538

EXAMPLE 814'-[(2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 50% of theory Melting point: >300° C. R_(f) -value: 0.16 (silicagel; methylene chloride/ethanol=9:1)

EXAMPLE 824'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 84% of theory Melting point: 285°-286° C. R_(f) -value: 0.55(silica gel; methylene chloride/methanol=9:1)

EXAMPLE 834'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 18% of theory Melting point: amorph. R_(f) -value: 0.29 (silicagel; methylene chloride/methanol=9:1) C₃₁ H₃₂ N₈ (516.66) mass spectrum:m/e=516

EXAMPLE 844'-[(2-n-Propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyland trifluoroacetic acid in methylene chloride.

EXAMPLE 854'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 1 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyland trifluoroacetic acid in methylene chloride.

EXAMPLE 864'-[(2-n-Propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

EXAMPLE 874'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 10 from4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

EXAMPLE 884'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

a) 3-Methyl-4-butyrylamino-5-nitro-acetophenone

32.6 g (148 mMol) of 3-methyl-4-butyrylamino-acetophenone are added inbatches to 300 ml of fuming nitric acid, with stirring, at -15° C. andstirred for a further 30 minutes at -15° C. The reaction mixture is thenpoured onto 3 liters of ice with stirring, the crude productprecipitated is suction filtered, washed with 400 ml of water, dried andpurified by recrystallisation from ethanol/diethylether (1:1).

Yield: 23.8 g (61.0% of theory), R_(f) value: 0.32 (silica gel;methylene chloride) R_(f) value: 0.48 (silica gel; methylenechloride/methanol=50:1)

b) 3-Methyl-4-butyrylamino-5-nitro-ω-bromoacetophenone

At ambient temperature, with stirring, a solution of 16.0 g (200 mMol)of bromine in 140 ml of dioxane is slowly added dropwise to a solutionof 23.8 g (90 mMol) of 3-methyl-4-butyrylamino-5-nitro-acetophenone in900 ml of dichloromethane so that the reaction mixture is constantlycompletely decolorised. It is then stirred for a further two hours, thenthe reaction mixture is evaporated to dryness in vacuo, the residue thusobtained is triturated with about 20 ml of dichloromethane/diethylether(1:1), suction filtered and then dried. 23 g (74% of theory) of3-methyl-4-butyrylamino-5-nitro-ω-bromoacetophenone are thus obtained,containing about 10% of starting material. The product is furtherreacted without any more purification. R_(f) value: 0.69 (silica gel;methylene chloride/methanol=50:1) R_(f) value: 0.84 (silica gel;methylene chloride/methanol=9:1)

c) 2-Butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene

A solution of 6.8 g (20 mMol) of3-methyl-4-butyrylamino-5-nitro-ω-bromoacetophenone in 20 ml offormamide is heated to 140 ° C. for 2 hours. The cooled solution is thenpoured into about 50 ml of 1N ammonia and stirred for about 15 minutes.The crude product precipitated is suction filtered, washed with about 50ml of water and dried. In this way, 4.4 g (75% of theory) of the productare obtained, which is further reacted without any more purification.R_(f) value: 0.29 (silica gel; methylene chloride/methanol=9:1)

d) 2-Butyrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene

1.3 g (9.5 mMol) of methyl iodide are added dropwise at ambienttemperature to a solution of 2.5 g (8.7 mMol) of2-butyrylamino-3-nitro-5-(imidazol-4-yl)-toluene and 5.2 g (30 mMol) ofpotassium carbonate dihydrate in 30 ml of dimethylsulphoxide at ambienttemperature and then stirred for 2 hours. The reaction mixture is thenstirred into about 150 ml of water and then extracted four times with 25ml of ethyl acetate. The organic extracts are washed with about 30 ml ofwater, dried and concentrated by evaporation. The crude product thusobtained is purified by column chromatography (300 g silica gel, eluant:methylene chloride/methanol=30:1).

Yield: 640 mg (24% of theory), R_(f) value: 0.54 (silica gel; methylenechloride/methanol=9:1)

e) 2-Butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene

640 mg (2.1 mMol) of2-butyrylamino-3-nitro-5-(1-methyl-imidazol-4-yl)-toluene arehydrogenated at ambient temperature under a hydrogen pressure of 5 barin 30 ml of methanol after the addition of about 200 mg of 20%palladium/charcoal. After all the water has been absorbed the catalystis filtered off and the filtrate is evaporated down. The crude productthus obtained is further reacted without any more purification.

Yield: 600 mg (100% of theory), R_(f) value: 0.23 (silica gel; methylenechloride/methanol=9:1)

f) 2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole

600 mg (2.1 mMol) of2-butyrylamino-3-amino-5-(1-methyl-imidazol-4-yl)-toluene are refluxedin 10 ml of glacial acetic acid for one hour. Then the mixture isevaporated to dryness in vacuo, the residue is mixed with about 15 ml ofwater, made alkaline with ammonia and extracted four times with about 10ml of ethyl acetate. The organic extracts are washed with about 15 ml ofwater, dried and finally evaporated down. The crude product thusobtained is further reacted without any more purification.

Yield: 420 mg (79% of theory), R_(f) value: 0.37 (silica gel; methylenechloride/methanol=9:1)

g) Tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate

280 mg (0.8 mMol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylateare added to a solution of 200 mg (0.79 mMol) of2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg(0.8 mMol) of potassium tert.butoxide in 5 ml of dimethylsulphoxide andthe mixture is stirred for 90 minutes at ambient temperature, thenstirred into about 40 ml of water, extracted four times with about 10 mlof ethyl acetate, then the organic extracts are washed with 10 ml ofwater, dried and evaporated to dryness. The crude product thus obtainedis purified by column chromatography (100 g silica gel; eluant;dichloromethane/methanol=30:1).

Yield: 230 mg (56% of theory), R_(f) value: 0.61 (silica gel; methylenechloride/methanol=9:1)

h)4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

A solution of 230 mg (0.44 mMol) of tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-carboxylateand 2 ml of trifluoroacetic acid in 10 ml of dichloromethane is stirredovernight at ambient temperature and then evaporated to dryness. Theresidue is dissolved in about 5 ml of dilute sodium hydroxide solution,the solution is neutralised with acetic acid, the precipitate formed issuction filtered, washed with water and dried.

Yield: 120 mg (59% of theory), Melting point: 293°-295° C. R_(f) value:0.39 (silica gel; methylene chloride/methanol=9:1)

EXAMPLE 894'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

a)4'-[(2-n-Propyl-4-methyl-6-(1-methylimidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl

218 mg (0.8 mMol) of 4'-bromomethyl-2-cyano-biphenyl are added to asolution of 200 mg (0.79 mMol) of2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazole and 90 mg(0.8 mMol) of potassium tert.butoxide in 6 ml of dimethylsulphoxide andthe mixture is stirred for 14 hours at ambient temperature. Then it isstirred into about 40 ml of water, extracted four times with about 10 mlof ethyl acetate, the organic extracts are washed with about 10 ml ofwater, dried and evaporated to dryness. The crude product thus obtainedis purified by column chromatography (100 g silica gel; eluant:dichloromethane/ethanol=50:1).

Yield: 240 mg (67% of theory), R_(f) value: 0.38 (silica gel; methylenechloride/ethanol=19:1)

b)4'-[(2-n-Propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

A solution of 222 mg (0.5 mMol) of4'-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl,660 mg (10 mMol) of sodium azide and 540 mg (10 mMol) of ammoniumchloride in 12 ml of pure dimethylformamide is heated to 140° C. for 18hours. The solution is then evaporated substantially to dryness and theproduct is isolated by column chromatography (60 g of silica gel,eluant: dichloromethane with 10% ethanol). The product thus obtained istaken up in about 10 ml of dilute ammonia solution and the solution isthen adjusted to pH 6 with acetic acid. A greasy residue is formed whichbecomes crystalline after the addition of a little ethyl acetate andseveral hours' stirring. The crystalline product is suction filtered,washed with about 5 ml of water and dried.

Yield: 61.0 mg (24.0% of theory), Melting point: 255°-2 57° C. C₂₉ H₂₈N₈ ×H₂ O (506.62) Calculated: C 68.75 H 5.97 N 22.12 Found: 68.90 5.9722.03 R_(f) value: 0.24 (silica gel; methylene chloride/methanol=9:1)

EXAMPLE 904'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 84.0% of theory, Melting point: 285°-286° C. R_(f) value: 0.55(silica gel; methylene chloride/methanol=9:1)

EXAMPLE 914'-[(2-n-Propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 74.0% of theory, Melting point: 258°-259° C. C₃₄ H₃₈ N₄ O₂(534.71) R_(f) value: 0.48 (silica gel; methylene chloride/methanol=9:1)Mass spectrum: m/e=534

EXAMPLE 924'-[(2-n-Propyl-4-methyl-6-(1-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-cyclopentylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 934'-[(2-n-Propyl-4-methyl-6-(1-cyclohexylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-cyclohexylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 944'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 44.0% of theory, Melting point: 226°-227° C. C₃₅ H₃₂ N₄ O₂(540.68) R_(f) value: 0.51 (silica gel; methylene chloride/methanol=9:1)Mass spectrum: m/e=540

EXAMPLE 954'-[(2-n-Propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(4-fluorobenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

The following compounds may be obtained analogously to Example 95:

4'-[(2-n-propyl-4-methyl-6-(1-(3-chlorobenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-(3,5-dimethoxybenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-(4-methylbenzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

4'-[(2-n-propyl-4-methyl-6-(1-(4-trifluoromethyl-benzyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

EXAMPLE 964'-[(2-n-Propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(2-phenylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 974'-[(2-n-Propyl-4-methyl-6-(1-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(2,2,2-trifluoroethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 984'-[(2-n-Propyl-4-methyl-6-(1-(3,3,3-trifluoropropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(3,3,3-trifluoropropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 994'-[(2-n-Propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 1004'-[(2-n-Propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

EXAMPLE 1014'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 59.0% of theory, Melting point: 279°-280° C. C₃₂ H₃₂ N₄ O₂(504.64) Calculated: C 76.16 H 6.39 N 11.10 Found: 76.41 6.37 11.20R_(f) value: 0.44 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=504

EXAMPLE 1024'-[(2-n-Propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 89 from4'-[(2-n-propyl-4-methyl-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyland sodium azide in dimethylformamide.

Yield: 18.0% of theory, Melting point: amorphous C₃₁ H₃₂ N₈ (516.66)R_(f) value: 0.29 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=516

EXAMPLE 1034'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

a)4'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl

To a solution of 300 mg (1.0 mMol) of2-n-propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazoleand 110 mg (1.0 mMol) potassium tert.butoxide in 20 ml ofdimethylsulphoxide are added 560 mg (1.0 mMol) of4'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl and themixture is stirred for 16 hours at ambient temperature, then stirredinto about 120 ml of water and extracted four times with 15 ml of ethylacetate. The organic extracts are washed with about 30 ml of water,dried and then evaporated to dryness. The crude product thus obtained ispurified by column chromatography (100 g silica gel, eluant: methylenechloride/methanol=30:1).

Yield: 460 mg (60% of theory), R_(f) value: 0.78 (silica gel; methylenechloride/methanol=9:1)

b)4'-[(2-n-Propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

A mixture of 460 mg (0.6 mMol) of4'-[(2-n-propyl-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland 10 ml of saturated methanolic hydrochloric acid is stirred for onehour at ambient temperature. The mixture is then evaporated to dryness,the residue is dissolved in dilute ammonia solution and washed withether. The aqueous phase is adjusted to pH 5 to 6 with acetic acid andsubsequently the solid precipitate is suction filtered. The crudeproduct thus obtained is purified by column chromatography (100 g silicagel, eluant: methylene chloride/methanol=15:1)

Yield: 130 mg (41% of theory), Melting point: amorphous C₃₂ H₃₂ N₈(528.67) R_(f) value: 0.32 (silica gel; methylene chloride/methanol=9:1)Mass spectrum: m/e=528

EXAMPLE 1044'-[(2-n-Propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(1-cyclobutylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland sodium azide in dimethylformamide.

EXAMPLE 1054'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 67.0% of theory, Melting point: 241°-243° C. C₂₉ H₂₇ N₃ O₃(465.56) Calculated: C 74.82 H 5.85 N 9.03 Found: 74.65 5.98 8.85 R_(f)value: 0.27 (silica gel; methylene chloride/ethanol=19:1)

EXAMPLE 1064'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland sodium azide in dimethylformamide.

EXAMPLE 1074'-[(2-n-Propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 87.0% of theory, Melting point: 281°-283° C. C₃₄ H₂₉ N₃ O₃(527.63) Calculated: C 77.40 H 5.54 N 7.96 Found: 77.09 5.71 7.76 R_(f)value: 0.18 (silica gel; methylene chloride/ethanol=19:1)

EXAMPLE 1084'-[(2-n-Propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(2-phenyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland sodium azide in dimethylformamide.

EXAMPLE 1094'-[(2-n-Propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(1-benzyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 45.0% of theory, Melting point: 168°-170° C. C₃₅ H₃₂ N₈ (564.70)R_(f) value: 0.37 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=564

EXAMPLE 1104'-[(2-n-Propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-Propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 61.0% of theory, Melting point: 126°-128° C. C₃₄ H₃₈ N₈ (558.74)R_(f) value: 0.31 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=558

EXAMPLE 1114'-[(2-Ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 69.0% of theory, Melting point: 175°-178° C. C₂₉ H₂₈ N₈ O(504.61) Calculated: C 6 9.03 H 5.59 N 22.21 Found: 68.85 5.58 21.97R_(f) value: 0.27 (silica gel; methylene chloride/ethanol=9:1) Massspectrum: m/e=504

EXAMPLE 1124'-[(2-Ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 38.0% of theory, Melting point: 220°-223° C. C₂₉ H₂₈ N₄ O₃(480.58) Calculated: C 72.48 H 5.87 N 11.66 Found: 72.36 6.05 11.41R_(f) value: 0.26 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=480

EXAMPLE 1134'-[(2-Ethoxy-5-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethoxy-5-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 44.0% of theory, Melting point: amorphous C₂₉ H₂₈ N₈ O (504.61)R_(f) value: 0.24 (silica gel; methylene chloride/ethanol=9:1) Massspectrum: m/e=504

EXAMPLE 1144'-[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 79.0% of theory, Melting point: from 190° C. (decomp.) C₃₅ H₃₈ N₄O₂ (546.71) R_(f) value: 0.36 (silica gel; methylenechloride/methanol=9:1) Mass spectrum: m/e=546

EXAMPLE 1154'-[(2-n-Propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(1-cycloheptyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 27.0% of theory, Melting point: 198°-201° C. C₃₅ H₃₈ N₈ (570.75)R_(f) value: 0.48 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=570

EXAMPLE 1164'-[(2-n-Propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 28.0% of theory, Melting point: 236°-238° C. C₃₅ H₄₀ N₄ O₂(548.73) R_(f) value: 0.61 (silica gel; methylene chloride/methanol=9:1)Mass spectrum: m/e=548

EXAMPLE 1174'-[(2-Ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 52.0% of theory, Melting point: 172°-173° C. C₃₁ H₃₀ N₄ O₃(506.61) Calculated: C 73.50 H 5.97 N 11.06 Found: 73.36 5.94 11.30R_(f) value: 0.52 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=506

EXAMPLE 1184'-[(2-Ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 42.0% of theory, Melting point: amorphous C₃₁ H₃₀ N₈ O (530.64)R_(f) value: 0.50 (silica gel; methylene chloride/methanol=9:1) Massspectrum: m/e=530

EXAMPLE 1194'-[(2-n-Propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(1-(1-n-propyl-n-butyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 12.0% of theory, Melting point: from 150° C. (sintering) C₃₅ H₄₀N₈ (572,76) R_(f) value: 0.34 (silica gel; methylenechloride/methanol=9:1) Mass spectrum: m/e=572

EXAMPLE 1204'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid hydrate

a) tert. Butyl4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate

A solution of 2.8 g (11 mMol) of2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15mMol) of potassium tert.butoxide in 60 ml of dimethyl-sulphoxide isstirred for 15 minutes at ambient temperature. Then 5.2 g (15 mMol) oftert.butyl 4'-bromomethyl-biphenyl-2-carboxylate are added and themixture is stirred for a further 14 hours at ambient temperature. Thenthe solution is stirred into about 150 ml of saturated sodium chloridesolution, the crude product precipitated is suction filtered andpurified by column chromatography (400 g of silica gel; eluant:methylene chloride with 1 to 2% ethanol).

Yield: 3.5 g (61.4% of theory), Melting point: amorphous R_(f) value:0.90 (silica gel; methylene chloride/ethanol=4:1)

b)4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid hydrate

A mixture of 1.5 g (3 mMol) of tert.butyl4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate,10 ml of 40% N-methylamine solution and 15 ml of N-methylformamide isheated for 10 hours to 200° C. in an autoclave. After cooling, thecontents of the autoclave are stirred with about 40 ml of water, thissuspension is adjusted to pH 6.5 with glacial acetic acid, then thecrude product precipitated is suction filtered and dissolved in 1Nsodium hydroxide solution. This solution is washed successively with 25ml of acetic acid and diethylether, then adjusted to pH 6 with 20%citric acid. The product precipitated is suction filtered, washed withabout 30 ml of water and dried, then triturated with diethylether anddried in a high vacuum.

Yield: 950 mg (68% of theory), Melting point: 239°-240° C. C₃₀ H₃₀ N₄ O₂×H₂ O (496.62) Calculated: C 72.55 H 6.49 N 11.28 Found: 72.62 6.6211.54 R_(f) value: 0.70 (silica gel; methylene chloride/ethanol=4:1)

EXAMPLE 1214'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

a)4'-[(2-n-Propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl

A solution of 2.8 g (11 mMol) of2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazole and 1.7 g (15mMol) of potassium tert.butoxide in 60 ml of dimethylsulphoxide isstirred for 15 minutes at ambient temperature. Then 6.0 g of (11 mMol)of 4'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are addedand the mixture is stirred for a further 3 hours at ambient temperature.Then the solution is stirred into about 150 ml of saturated sodiumchloride solution, the crude product precipitated is suction filteredand purified by column chromatography (500 g of silica gel; eluant:petroleum ether/ethyl acetate=1:1)

Yield: 3.6 g (45% of theory)

b)4'-[(2-n-Propyl-4-methyl-6-(1,2-dimethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

A mixture of 3.6 g (4,9 mMol) of4'[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenyl-methyl-tetrazol-5-yl)-biphenyl,20 ml of 40% N-methylamine solution and 30 ml of N-methylformamide isheated to 200° C. for 10 hours in an autoclave. After cooling, thecontents of the autoclave are stirred with about 50 ml of water, thissuspension is adjusted to pH 6.5 with 20% citric acid, then the crudeproduct precipitated is suction filtered and purified by columnchromatography (200 g silica gel; eluant: methylene chloride with 5 to20% ethanol).

Yield: 1.0 g (41% of theory), Melting point: from 195° C. sintering C₃₀H₃₀ N₈ ×H₂ O (520.6) Calculated: C 69.21 H 6.19 N 21.52 Found: 68.996.26 21.37 Mass spectrum: m/e=502

EXAMPLE 1224'-[(2-Ethyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 49% of theory, Melting point: 165°-167° C. C₃₀ H₃₀ N₄ O₃ (494.60)Calculated: C 72.85 H 6.11 N 11.33 Found: 72.62 6.27 11.35 Massspectrum: m/e=494

EXAMPLE 1234'-[(2-Cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert. butyl4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 78% of theory, Melting point: 179°-181° C. C₃₁ H₃₀ N₄ O₃ (506.61)Calculated: C 73.50 H 5.97 N 11.06 Found: 73.37 6.02 11.02 Massspectrum: m/e=506

EXAMPLE 1244'-[(2-n-Propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert. butyl4'-[(2-n-propyl-4-methyl-6-(1-aminocarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 26% of theory, Melting point: 190°-192° C. C₃₀ H₂₉ N₅ O₃ (507.60)R_(f) value: 0.44 (silica gel; methylene chloride/methanol=8:2)

EXAMPLE 1254-[(2-n-Propyl-4-methyl-6-(1-ethoxycarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-ethoxycarbonylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 18% of theory, Melting point: 223°-224° C. C₃₂ H₃₂ N₄ O₄ (536.63)R_(f) value: 0.69 (silica gel; methylene chloride/methanol=8:2) Massspectrum: m/e=536

EXAMPLE 1264'-[(2-Cyclopropyl-4-methyl-6-(1-(2-hydroxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

A solution of 500 mg (1.0 mMol) of4'-[(2-cyclopropyl-4-methyl-6-(1-(2-methoxyethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid and 1.5 g (6.0 mMol) of boron tribromide in 50 ml of methylenechloride is stirred for 16 hours at ambient temperature, then mixed withabout 30 ml of water and stirred vigorously for another 10 minutes. Thismixture is evaporated to dryness and the residue is refluxed in about 40ml of ethanol for 10 minutes. The mixture is evaporated to dryness oncemore, the residue is dissolved in about 30 ml of 2N ammonia solution andthis solution is adjusted to pH 5-6 with 2N acetic acid. The crudeproduct precipitated is suction filtered and purified by columnchromatography (80 g silica gel; eluant: methylenechloride/methanol=4:1).

Yield: 150 mg (30% of theory), Melting point: 220°-222° C. C₃₀ H₂₈ N₄ O₃(492.58) R_(f) value: 0.20 (silica gel; methylene chloride/methanol=9:1)Mass spectrum: m/e=492

EXAMPLE 1274-[(2-n-Propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert. butyl4'-[(2-n-propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 54% of theory, Melting point: 259°-261° C. C₃₄ H₃₇ N₅ O₃ (563.70)Calculated: C 72.44 H 6.62 N 12.42 Found: 72.68 6.65 12.53 Massspectrum: m/e=563

EXAMPLE 1284'-[(2-n-Propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(2-methoxyethoxy-2-ethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 49% of theory, Melting point: 192°-194° C. C₃₃ H₃₆ N₄ O₄ (552.67)Calculated: C 71.72 H 6.57 N 10.14 Found: 71.52 6.36 10.25 R_(f) value:0.36 (silica gel; dichloromethane/methanol=9:1) Mass spectrum: m/e=552

EXAMPLE 1294'-[(2-n-Propyl-4-methyl-6-(1-(3-dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid dihydrochloride-pentahydrate

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(1-(3-dimethylaminopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 12% of theory, Melting point: from 128° C. (decomp.) C₃₃ H₃₇ N₅O₂ ×2 HCl×5 H₂ O (535.70) R_(f) value: 0.20 (silica gel;dichloromethane/methanol=9:1) Mass spectrum: m/e=535

EXAMPLE 1304'-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 32% of theory, Melting point: 248°-250° C. C₂₉ H₂₇ N₃ O₂ S(481.62) Calculated: C 72.32 H 5.65 N 8.72 Found: 72.21 5.83 8.67 R_(f)value: 0.26 (silica gel; dichloromethane/methanol=9:1) Mass spectrum:m/e=481

EXAMPLE 1314'-[(2-n-Propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-dihydrochloride

Prepared analogously to Example 103 from4'-[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 91% of theory, Melting point: from 219° C. (decomp.) C₂₉ H₂₉ C₁₂N₇ S (578.58) Calculated: C 60.20 H 5.05 N 16.95 Cl 12.25 Found: 59.965.19 16.63 12.42 R_(f) value: 0.32 (silica gel;dichloromethane/methanol=9:1) Mass spectrum: m/e=505

EXAMPLE 1324'-[(2-Ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.

Yield: 27% of theory, Melting point: 201°-20 2° C. C₃₃ H₃₅ N₅ O₃(549.65) Calculated: C 72.11 H 6.42 N 12.74 Found: 72.00 6.48 12.62R_(f) value: 0.36 (silica gel; methylene chloride/methanol=9:1) massspectrum: m/e=549

EXAMPLE 1334'-[(2-Ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

Prepared analogously to Example 103 from4'-[(2-ethyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 14% of theory, Meling point: above 180° C. (decomp.) C₃₃ H₃₅ N₉O×H₂ O (573.68) Calculated: C 66.98 H 6.30 N 21.31 Found: 66.87 6.3621.22 R_(f) value: 0.31 (silica gel; methylene chloride/methanol=9:1)mass spectrum: m/e=573

EXAMPLE 1344'-[(2-Ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 66% of theory, Melting point: above 185° C. (decomp.) C₃₀ H₂₉ N₅O₃ (507.59) Calculated: C 70.99 H 5.76 N 13.80 Found: 70.73 5.72 13.66mass spectrum: m/e=507

EXAMPLE 1354'-[(2-Ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 42% of theory, Melting point: above 191° C. (decomp.) C₃₀ H₂₉ N₉O (531.63) Calculated: C 67.78 H 5.50 N 23.71 Found: 67.79 5.40 23.66R_(f) value: 0.20 (silica gel; methylene chloride/methanol=8:2) massspectrum: m/e=531

EXAMPLE 1364'-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 60% of theory, Melting point: 215°-217° C. C₃₃ H₃₅ N₅ O₂ (533.67)Calculated: C 74.27 H 6.61 N 13.12 Found: 74.03 6.85 13.11 R_(f) value:0.30 (silica gel; methylene chloride/methanol=8:2) mass spectrum:m/e=533

EXAMPLE 1374'-[(2-Ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethyl-4-methyl-6-(1-(2-N-pyrrolidinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield 38% of theory, Melting point: above 128° C. (sintering) C₃₃ H₃₅ N₉(551.71) Calculated: C 71.84 H 6.39 N 22.85 Found: 71.63 6.20 22.49R_(f) value: 0.23 (silica gel; methylene chloride/methanol=8:2)

EXAMPLE 1384'-[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid-dihydrochloride

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 32% of theory, Melting point 255°-257° C. (decomp.) C₃₃ H₃₇ N₅ O₂×2 HCL (608.60) R_(f) value: 0,24 (silica gel; methylenechloride/methanol=9:1)

EXAMPLE 1394'-[(2-Ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethyl-4-methyl-6-(1-(2-diethylaminoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 51% of theory Melting point: 191°-193° C. C₃₃ H₃₇ H₉ (559.70)Calculated C 70.81 H 6.66 N 22.52 Found: 70.59 6.66 22.58 R_(f) value:0,30 (silica gel; methylene chloride/methanol=8:2)

EXAMPLE 1404'-[(2-Ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 88 from tert.butyl4'-[(2-ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 19% of theory, Melting point: amorphous C₃₅ H₃₉ N₅ O₂ (561.73)Calculated: C 74.84 H 7.00 N 12.47 Found: 74.61 6.92 12.31 R_(f) value:0.34 (silica gel; methylene chloride/methanol=8:2)

EXAMPLE 1414'-[(2-Ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 103 from4'-[(2-ethyl-4-methyl-6-(1-(3-N-piperidinopropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 71% of theory, Melting point: above 140° C. (decomp.) C₃₅ H₃₉ N₉(585.76) Calculated: C 71.77 H 6.71 N 21.52 Found: 71.58 6.68 21.44R_(f) value: 0.22 (silica gel; methylene chloride/methanol=8:2)

EXAMPLE 142 Methyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

a) Methyl4'-[(2-n-propyl-4-methyl-6-amidino-1H-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate

Hydrogen chloride gas is piped into a solution of 6.2 g (14.6 mMol) ofmethyl4'-[[2-n-propyl-4-methyl-6-cyano-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylatein 750 ml of absolute methanol for 3 hours at ambient temperature andthe mixture is stirred for a further 2 hours at ambient temperature.After removal of the solvent the mixture is evaporated down in vacuo,the residue is taken up twice with 50 ml of methanol and 50 ml of etherand evaporated down once more. Then the residue is dissolved in 750 mlof absolute methanol and mixed with 30 g of ammonium carbonate. After 12hours at ambient temperature, 50 g of silica gel (particle size:0.06-0.3 mm) are added. After filtration and evaporation of the filtratethe residue is chromatographed on silica gel (particle size 0.032-0.063mm) using as eluant mixtures of methylene chloride and methanol ofincreasing polarity (9:1, 4:1, 3:1 and 1:1). The uniform fractions arecombined and evaporated down.

Yield: 4.3 g (57% of theory), Foam, R_(f) value: 0.14 (silica gel;methylene chloride/ethanol=9:1)

b) Methyl4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

0.5 g (1.0 mMol) of methyl4'-[(2-n-propyl-4-methyl-6-amidino-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate,0.13 g (1.0 mMol) of 2-chloro-cyclohexanone and 10 ml of liquid ammoniaare heated to 60° C. in a bomb for 15 hours. After cooling andevaporation of the ammonia the residue is dissolved inmethanol/methylene chloride (2:1) and chromatographed on silica gel(particle size: 0.032-0.063 mm), using as eluant mixtures of methylenechloride and ethanol of increasing polarity (19:1 and 9:1). The uniformfractions are combined and evaporated down.

Yield: 0.1 g (19% of theory), Foam, R_(f) value: 0.50 (silica gel;methylene chloride/ethanol=9:1)

EXAMPLE 1434'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

0.1 g (0.2 mMol) of methyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand 10 mg (0.02 mMol) of hexadecyl-tributylphosphonium bromide are takenup in 10 ml of (48%) hydrobromic acid and heated to 110° C. for 15minutes. After cooling, 20 ml of ether are poured over and the mixtureis diluted with 10 ml of water. After extraction the organic phase isseparated off. The aqueous phase is adjusted to pH 7 with ammonia, theprecipitate thus formed is suction filtered, washed with water and takenup in methylene chloride/ethanol (4:1). The solvent is evaporated off,the residue is triturated with ether and dried. The crude product ischromatographed on silica gel (particle size: 0.032-0.063 mm), using aseluant methylene chloride/ethanol (9:1). The uniform fractions arecombined and evaporated down. The residue is triturated with ether anddried.

Yield: 64 mg (64% of theory), Melting point: 231°-235° C. (decomp.) C₃₂H₃₂ N₄ O₂ (504.64) Mass spectrum: (M+H)⁺ =505

EXAMPLE 1444'-[[2-n-Propyl-4-methyl-6-(5,5-spiro-cyclopentano)-dihydroimidazol-4-on-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

0.05 g (0.1 mMol) of methyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateare dissolved in 4 ml of ethanol, mixed with 2 ml of 1N sodium hydroxidesolution and stirred for 4 days at ambient temperature. After theaddition of 4 ml of water the pH is adjusted to 6 using glacial aceticacid, the precipitate formed is suction filtered, washed with water anddried over potassium hydroxide. The crude product is chromatographed onsilica gel (particle size: 0.032-0.063 mm), using as eluant methylenechloride/ethanol/glacial acetic acid (50:1:0.1 and 30:1:0.1). Theuniform fractions are combined and evaporated down. The residue istriturated with ether and dried.

Yield: 30 mg (59% of theory), Melting point: 310°-311° C. (decomp.) C₃₂H₃₂ N₄ O₃ (520.64) Mass spectrum: (M+H)⁺ =521

EXAMPLE 145 Tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

a)2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzoxazol-2-yl)-1H-benzimidazol

2.17 g (10 mMol) of 2-n-propyl-4-methyl-6-aminocarbonyl-1H-benzimidazoleand 10.25 g (77 mMol) of 2-chloro-cyclohexanone are heated to 190° C.for one hour. After cooling to ambient temperature the reaction mixtureis triturated with ether and suction filtered. The residue is taken upin water and mixed with concentrated ammonia. Then it is extracted withmethylene chloride, the organic phase is washed with water, dried overmagnesium sulphate and evaporated down. The residue is chromatographedon silica gel (particle size: 0.032-0.063 mm) using as eluant mixturesof methylene chloride and ethanol of increasing polarity (50:1, 25:1 and20:1). The uniform fractions are combined and evaporated down.

Yield: 1.9 g (64% of theory), Foam, R_(f) value: 0.20 (silica gel; ethylacetate)

b) Tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

3.3 g (11 mMol) of2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazoleare dissolved in 15 ml of dimethylformamide and at 5°-10° C. 1.5 g (13.2mMol) of potassium tert.butoxide are added in batches. After 15 minutesat 5° C. 4.6 g (13.2 mMol) of tert.butyl4'-bromomethyl-biphenyl-2-carboxylate are added. After a further 45minutes at 5° C. the reaction mixture is stirred into 200 ml of water.The precipitate formed is suction filtered, washed with water and takenup in 200 ml of ethyl acetate. The solution is washed with water andwith saturated sodium chloride solution, dried over magnesium sulphateand evaporated down. The residue is chromatographed on silica gel(particle size: 0.032-0.063 mm) using as eluant methylenechloride/ethanol (50:1). The uniform fractions are combined andevaporated down.

Yield: 4.8 g (78% of theory), Foam, R_(f) value: 0.23 (silica gel;methylene chloride/ethanol=49:1)

EXAMPLE 1464'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

2.0 g (3.56 mMol) of tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate,16 ml (40 mMol) of formamide and 40 ml of ammonia (liquid) are heated to200° C. in the bomb for 14 hours. After cooling, the reaction mixture isdiluted with water, the precipitate thus formed is suction filtered. Thefiltrate is adjusted to pH 6 with glacial acetic acid, the precipitateformed is removed by centrifuging and washed with water. The residue istaken up in 50 ml of 2N hydrochloric acid. By the addition ofconcentrated ammonia the pH is adjusted to 6 and the precipitate thusformed is suction filtered, washed with water and dried.

Yield: 1.3 g (72% of theory), Melting point: from 235° C. (decomp.)

EXAMPLE 1474'-[[2-n-Propyl-4-methyl-6-(1,3-dimethyl-5,6,7,8-tetrahydrobenzimidazoliumiodide-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid

0.85 g (1.7 mMol) of4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid are dissolved in 9 ml of dimethylsulphoxide, mixed with 420 mg (3.7mMol) of potassium tert.butoxide at 5° C. and stirred for 10 minutes.After the addition of 570 mg (4.0 mMol) of methyliodide the reactionmixture is heated to 70° C. for 25 minutes. After cooling, it is pouredonto ice, the precipitate formed is suction filtered and washed withwater. The residue is taken up in 50 ml of ethanol, combined with 12 mlof 1N sodium hydroxide solution and stirred for 5 days at ambienttemperature. The solvent is evaporated off in vacuo, the residue ismixed with ice and acidified with aqueous citric acid (5%). Theprecipitate thus formed is suction filtered, washed with water anddried.

Yield: 470 mg (42% of theory), Melting point: 240°-242° C. (decomp.) C₃₄H₃₇ N₄ O₂ I (660.61) Calculated: C 61.82 H 5.65 N 8.48 Found: 61.69 5.888.72

EXAMPLE 1484'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methylformamide/methylamine.

Yield: 27% of theory, Melting point: 183°-186° C. C₃₃ H₃₄ N₄ O₂ ×H₂ O(536.68) Calculated: C 73.85 H 6.76 N 10.44 Found: 74.22 6.97 10.48

EXAMPLE 1494'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl-semihydrate

a)4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl

Prepared analogously to Example 145b from2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazoleand 4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyl. Oil,R_(f) value: 0.67 (silica gel; ethyl acetate)

b)4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl-semihydrate

Prepared analogously to Example 146 from2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyland formamide/ammonia.

Yield: 70% of theory, Melting point: from 230° C. (decomp.) C₃₂ H₃₂ N₈×0.5 H₂ O (537.68) Calculated: C 71.48 H 6.19 N 20.84 Found: 71.43 6.4621.20

EXAMPLE 1504'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl-semihydrate

Prepared analogously to Example 146 from4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)biphenyland N-methyl-formamide/methylamine.

Yield: 63% of theory, Melting point: from 240° C. (decomp.) C₃₃ H₃₄ N₈×0.5 H₂ O (551.71) Calculated: C 71.84 H 6.40 N 20.31 Found: 71.63 6.4520.64

EXAMPLE 1514'-[[2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-benzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

1.2 g (24 mMol) of tert.butyl2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateare dissolved in 25 ml of methylene chloride, mixed with 8.5 ml oftrifluoroacetic acid and stirred for 3 hours at ambient temperature.Then the solvent is evaporated off in vacuo, the residue is mixed withice and made alkaline with conc. ammonia. After one hour the pH isadjusted to 5 by the addition of citric acid. The precipitate thusformed is suction filtered, washed with water and dried. The crudeproduct is purified on silica gel (particle size: 0.032-0.063 nm) usingethyl acetate as eluant. The uniform fractions are combined andevaporated down.

Yield: 33% of theory, Melting point: 229°-232° C. (decomp.) C₃₂ H₃₁ N₃O₃ (505.62) Mass spectrum: M⁺ =505

EXAMPLE 1524'-[[2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

a)2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazole

Prepared analogously to Example 145a from2-ethyl-4-methyl-6-aminocarbonyl-1H-benzimidazole and2-chloro-cyclohexanone.

Yield: 60% of theory, Oil, R_(f) value: 0.17 (silica gel; ethyl acetate)

b)4'-[[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydro-benzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 145b from2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazoleand 4'-bromomethyl-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl.

Yield: 63% of theory, Oil, R_(f) value: 0.69 (silica gel; ethyl acetate)

c)4'-[[2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

Prepared analogously to Example 146 from4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland N-methyl-formamide/methylamine.

Yield: 51% of theory, Melting point: from 180° C. (decomp.) C₃₂ H₃₂ N₈×H₂ O (546.69) Calculated×H₂ O: C 70.31 H 6.27 N 20.50 Found: 70.07 6.5520.60 Mass spectrum: M⁺ =528

EXAMPLE 1534'-[[2-Ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

a) tert.butyl4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

Prepared analogously to Example 145b from2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazoleand tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate.

Yield: 77% of theory, Melting point: 160°-162° C.

b)4'-[[2-ethyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methylformamide/methylamine.

Yield: 34% of theory, Melting point: 292°-300° C. (decomp.) C₃₂ H₃₂ N₄O₂ ×H₂ O (522.66) Calculated×H₂ O: C 73.54 H 6.56 N 10.72 Found: 73.386.76 10.67 Mass spectrum: M⁺ =504

EXAMPLE 1544'-[[2-Ethyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-formylanilide/aniline.

Yield: 13% of theory, Melting point: 255°-257° C. (decomp.) C₃₇ H₃₄ N₄O₂ ×H₂ O (584.73) Calculated×H₂ O: C 76.00 H 6.20 N 9.58 Found: 76.366.18 9.59 Mass spectrum: M⁺ =566

EXAMPLE 1554'-[[2-n-Propyl-4-methyl-6-(1-phenyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-formylanilide/aniline.

Yield: 23% of theory, Melting point: 258°-260° C. (decomp.) C₃₈ H₃₆ N₄O₂ ×1/2 H₂ O (589.75) Calculated×1/2 H₂ O: C 77.39 H 6.32 N 9.50 Found:77.03 6.30 9.39 Mass spectrum: M⁺ =580

EXAMPLE 1564'-[[2-n-Propyl-4-methyl-6-(1-benzyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-benzylformamide/benzylamine.

Yield: 54% of theory, Melting point: 256°-258° C. (decomp.) C₃₉ H₃₈ N₄O₂ (594.77) Calculated: C 78.76 H 6.44 N 9.42 Found: 78.50 6.49 9.35Mass spectrum: M⁺ =594

EXAMPLE 1574'-[[2-n-Propyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-sesquihydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-ethylformamide/ethylamine.

Yield: 17% of theory, Melting point: from 228° C. (decomp.) C₃₄ H₃₆ N₄O₂ ×1.5 H₂ O (559.71) Calc.×1.5 H₂ O: C 72.96 H 7.02 N 10.01 Found:73.04 6.90 9.77 Mass spectrum: M⁺ =532

EXAMPLE 1584'-[[2-Ethyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-isopropylformamide/isopropylamine.

Yield: 2% of theory, Melting point: 197° C. C₃₄ H₃₆ N₄ O₂ (532.69) Massspectrum: M⁺ =532

EXAMPLE 1594'-[[2-n-Propyl-4-methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand isobutylamine/water.

Yield: 5% of theory, C₃₆ H₄₀ N₄ O₂ (560.75) Mass spectrum: (M+H)⁺ =561

EXAMPLE 1604'-[[2-n-Propyl-4-methyl-6-(1,3-dibenzyl-5,6,7,8-tetrahydrobenzimidazoliumacetate-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

Prepared analogously to Example 147 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand benzylbromide/sodium hydroxide solution/glacial acetic acid.

Yield: 76% of theory, Melting point: sintering from 80° C. C₄₆ H₄₄ N₄ O₂×CH₃ COOH×1/2 H₂ O (753.95) Calc.×CH₃ COOH×1/2 H₂ O: C 76.47 H 6.55 N7.43 Found: 76.46 6.65 7.76 Mass spectrum: M⁺ =684

EXAMPLE 1614'-[[2-n-Propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

Prepared analogously to Example 147 from4'-[[2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid and ethyl bromoacetate/sodium hydroxide solution.

Yield: 34% of theory, Melting point: 239°-242° C. C₃₄ H₃₄ N₄ O₄ ×1/2 H₂O (571.69) Calc.×1/2 H₂ O: C 71.43 H 6.17 N 9.80 Found: 71.39 6.19 9.81Mass spectrum: M⁺ =562

EXAMPLE 1624'-[[2-Cyclopropyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methyl-formamide/methylamine.

Yield: 50% of theory, Melting point: 285°-289° C. C₃₃ H₃₂ N₄ O₂ ×1/2 H₂O (525.66) Calculated: C 75.40 H 6.33 N 10.66 Found: 75.24 6.44 10.42Mass spectrum: M⁺ =516

The following compounds may be obtained analogously to the precedingExamples:

(1)4'-[[2-cyclopropyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(2)4'-[[2-ethoxy-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

(3)4'-[[2-ethoxy-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(4)4'-[[2-ethyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(5)4'-[[2-n-propyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

(6)4'-[[2-n-propyl-4-methyl-6-(1-isopropyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(7)4'-[[2-ethyl-4-methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

(8)4'-[[2-ethyl-4-methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(9)4'-[[2-n-propyl-4-methyl-6-(1-isobutyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(10)4'-[[2-n-propyl-4-methyl-6-(1-carboxymethyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

(11)4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5-trimethyleneimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

(12)4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5-trimethyleneimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)biphenyl

EXAMPLE 1634'-[[2-Ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 151 from4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyland hydrochloric acid in methanol.

Yield: 15% of theory, Melting point: 140°-142° C. (decomp.) C₃₁ H₂₉ N₇ O(515.63) Mass spectrum: (M+H)⁺ =516

EXAMPLE 1644'-[[2-Ethyl-4-methyl-6-(1-ethyl-5,6,7,8-tetrahydro-benzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl-hydrate

Prepared analogously to Example 146 from4'-[[2-ethyl-4-methyl-6-(5,6,7,8-tetrahydrobenzoxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyland N-ethyl-formamide/ethylamine.

Yield: 25% of theory, Melting point: from 180° C. (decomp.) C₃₃ H₃₄ N₈×H₂ O (560.72) Calculated: C 70.68 H 6.47 N 19.99 Found: 70.46 6.4419.56 Mass spectrum: M⁺ =542

EXAMPLE 1654'-[[2-n-Propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid ditrifluoroacetate

Prepared analogously to Example 151 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 60% of theory, Melting point: 158°-159° C. C₃₀ H₃₁ N₃ O₃ ×2 CF₃COOH (709.64) Calculated: C 57.55 H 4.69 N 5.92 Found: 57.76 4.72 6.02Mass spectrum: M⁺ =481

EXAMPLE 1664'-[[2-n-Propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

a) Tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-benzoylethyl)-methylaminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

To a solution of 1.0 g (2.0 mMol) of tert.butyl4'-[[2-n-propyl-4-methyl-6-chlorocarbonyl-1H-benzimidazol-1-yl]-methyl]-biphenyl-carboxylatein 20 ml of methylene chloride are added 20 ml of toluene and 0.44 g(2.2 mMol) of 2-methylamino-propiophenone. The reaction mixture isheated to 85° C. and 10 ml of pyridine are added dropwise within 4hours. Then the reaction mixture is evaporated down, the residue ismixed with ice water and extracted twice with methylene chloride. Thecombined organic phases are dried over magnesium sulphate and evaporateddown. The crude product is chromatographed on silica gel (particle size:0.032-0.063 mm) using as eluant methylene chloride to start with andlater methylene chloride/ethanol/ammonia (50:1:0.25 and 25:1:0.01). Theuniform fractions are combined and evaporated down.

Yield: 1.0 g (79% of theory), Foam, R_(f) value: 0.50 (silica gel;methylene chloride/ethanol=9:1)

b) Tert.butyl4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

A solution of 1.0 g (1.5 mMol) of tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-benzoyl-ethyl)-methylaminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand 15 g of ammonium acetate in 80 ml of glacial acetic acid is refluxedfor 2.5 hours. Then the reaction mixture is evaporated down to half, theresidue is mixed with ice water and extracted twice with ethyl acetate.The combined organic phases are washed with water, dried over magnesiumsulphate and evaporated down. The crude product is chromatographed onsilica gel (particle size: 0.032-0.063 mm) using as eluant methylenechloride with increasing amounts of ethanol (3%, 10% and 20%). Theuniform fractions are combined and evaporated down.

Yield: 0.68 g (74% of theory), Foam, R_(f) value: 0.40 (silica gel;methylene chloride/ethanol=19:1)

c)4'-[[2-n-Propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

Prepared analogously to Example 151 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-phenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 90% of theory, Melting point: from 152° C. (decomp.) C₃₆ H₃₃ N₄O₂ ×H₂ O (572.72) Calculated: C 75.50 H 6.34 N 9.78 Found: 75.95 6.489.92 Mass spectrum: M⁺ =554

EXAMPLE 1674'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-sesquihydrate

a) Tert.butyl4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

Prepared analogously to Example 166b from tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-benzoyl-benzyl)-methylaminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand ammonium acetate in glacial acetic acid.

Yield: 27% of theory, Oil, R_(f) value: 0.40 (silica gel; methylenechloride/ethanol=19:1)

b)4'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-sesquihydrate

Prepared analogously to Example 151 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(1-methyl-4,5-diphenyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 60% of theory, Melting point: 325°-328° C. (decomp.) C₄₁ H₃₆ N₄O₂ ×1.5 H₂ O (643.79) Calculated: C 76.49 H 6.11 N 8.70 Found: 76.536.15 8.75 Mass spectrum: M⁺ =616

EXAMPLE 1684'-[[2-n-Propyl-4-methyl-6-(5-methyl-4-isopropyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-dihydrate-acetate

a) Tert.butyl4'-[[2-n-propyl-4-methyl-6-(5-methyl-4-isopropyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

Prepared analogously to Example 166b from tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-acetyl-2-methyl-n-propyl)-methyl-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand ammonium acetate in glacial acetic acid.

Yield: 45% of theory, Oil, R_(f) value: 0.10 (silica gel; ethylacetate/petroleum ether=2:1)

b)4'-[[2-n-Propyl-4-methyl-6-(5-methyl-4-isopropyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-dihydrate-acetate

Prepared analogously to Example 151 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(5-methyl-4-isopropyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 75% of theory, Melting point: from 155° C. (decomp.) C₃₂ H₃₄ N₄O₂ ×CH₃ COOH×2 H₂ O (602.74) Calculated: C 67.75 H 7.02 N 9.30 Found:67.69 7.02 9.53 Mass spectrum: M⁺ =506

EXAMPLE 1694'-[[2-n-Propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-ditrifluoroacetate

a) Tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

A mixture of 0.43 g (0.8 mMol) of tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,4-dimethyl-oxazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand 0.67 ml (5.8 mMol) of 1,2-diaminopropane is heated to 120° C. for 48hours. The yellow solid obtained after cooling to ambient temperature isstirred with water for 1 hour, suction filtered and dried. The crudeproduct is chromatographed on silica gel (particle size: 0.032-0.063 mm)using as eluant methylene chloride/ethanol/ammonia (50:1:0.05, 20:1:0.02and 7:1:0.07). The uniform fractions are combined and evaporated down.

Yield: 0.26 g (62% of theory), Foam, R_(f) value: 0.20 (silica gel;methylene chloride/ethanol=9:1+ammonia)

b)4'-[[2-n-Propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-ditrifluoroacetate

Prepared analogously to Example 151 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 72% of theory, Melting point: 115°-118° C. (decomp., sinters from100° C.) C₂₉ H₃₀ N₄ O₂ ×2 CF₃ COOH (694.63) Calculated: C 57.06 H 4.64 N8.07 Found: 57.02 5.02 8.13 Mass spectrum: M⁺ =466

EXAMPLE 1704'-[[2-n-Propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

3.9 g (6.7 mMol) of tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-acetyl-2-methyl-n-propyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateare dissolved in 50 ml of phosphorusoxychloride and stirred for 2.5hours at 105° C. Then the phosphorusoxychloride is removed, the residueis decomposed with water at 80° C. and, after cooling, mixed with conc.ammonia. The pH is adjusted to 5 by the addition of glacial acetic acid,the precipitate thus formed is suction filtered, washed with water,taken up in methylene chloride/methanol (9:1) and dried over magnesiumsulphate. The crude product is chromatographed on silica gel (particlesize: 0.032-0.063 mm) using as eluant petroleum ether/ethylacetate/glacial acetic acid (1:1:0.002) and methylenechloride/ethanol/glacial acetic acid (20:1:0.002). The uniform fractionsare combined, evaporated down, triturated with ether and suctionfiltered.

Yield: 2.4 g (71% of theory), Melting point: 222°-223° C. C₃₂ H₃₃ N₃ O₃(507.64) Calculated: C 75.71 H 6.55 N 8.28 Found: 75.61 6.59 8.36 Massspectrum: M⁺ =507

EXAMPLE 1714'-[[2-n-propyl-4-methyl-6-(4-isopropyl-1,5-dimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid×1.25 water

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methylformamide/methylamine.

Yield: 38% of theory, Melting point: from 150° C. (decomp.) C₃₃ H₃₆ N₄O₂ ×1.25 H₂ O (543.20) Calculated: C 72.97 H 7.14 N 10.32 Found: 72.957.02 9.94 Mass spectrum: M⁺ =520

EXAMPLE 1724'-[[2-n-propyl-4-methyl-6-(1-ethyl-4-isopropyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-ethylformamide/ethylamine.

EXAMPLE 1734'-[[2-n-Propyl-4-methyl-6-(1-isopropyl-4-isopropyl-5-methylimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-isopropylformamide/isopropylamine.

EXAMPLE 1744'-[[2-n-Propyl-4-methyl-6-(1-cyclohexyl-4-isopropyl-5-methylimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-cyclohexyl-formamide/cyclohexylamine.

Yield: 10% of theory, C₃₈ H₄₄ N₄ O₂ (588.80) R_(f) value: 0.24 (silicagel; methylene chloride/ethanol/acetic acid=9:1:0.01) Mass spectrum:(M+H)⁼ 589

EXAMPLE 1754'-[[2-n-Propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4-isopropyl-5-methyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-semihydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isopropyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-dimethylamino-ethyl)-formamide/2-dimethylamino-ethylamine.

Yield: 48% of theory, Melting point: 192°-195° C. (decomp.) C₃₆ H₄₃ N₅O₂ ×0.5 H₂ O (586.79) Calculated: C 73.69 H 7.56 N 11.93 Found: 73.537.55 11.94 Mass spectrum: M⁺ =577

EXAMPLE 1764'-[[2-n-Propyl-4-methyl-6-(1,5-dimethyl-4-isobutyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methylformamide/methylamine.

Yield: 64% of theory, Melting point: 155°-157C (decomp.) C₃₄ H₃₈ N₄ O₂×0.75 H₂ O (548.22) Calculated: C 74.49 H 7.28 N 10.22 Found: 74.45 7.2910.35 Mass spectrum: M⁺ =534

EXAMPLE 1774'-[[2-n-Propyl-4-methyl-6-(1-ethyl-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid×0.25 water

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-ethylformamide/ethylamine.

Yield: 62% of theory, Melting point: 239°-241° C. C₃₃ H₃₅ N₃ O₃ ×0.25 H₂O (526.17) Calc.×0.25 H₂ O: C 75.33 H 6.80 N 7.99 Found: 75.35 6.75 7.96Mass spectrum: M⁺ =527

EXAMPLE 1784'-[[2-n-Propyl-4-methyl-6-(1-tert.butyl-4-isobutyl-5-methylimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-tert.butyl-formamide/tert.butylamine.

EXAMPLE 1794'-[[2-n-Propyl-4-methyl-6-(1-benzyl-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-benzyl-formamide/benzylamine.

EXAMPLE 1804'-[[2-n-Propyl-4-methyl-6-[1-(2-morpholino-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-morpholino-ethyl)-formamide/2-morpholino-ethylamine.

Yield: 30% of theory, Melting point: 201°-203° C. (decomp.) C₃₉ H₄₇ N₅O₃ (633.85) Calculated: C 73.90 H 7.47 N 11.05 Found: 73.65 7.45 11.07Mass spectrum: M⁺ =633

EXAMPLE 1814'-[[2-n-propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-hydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-methoxy-ethyl)-formamide/2-methoxy-ethylamine.

Yield: 29% of theory, Melting point: 135°-137C (decomp., sintering from110 _C) C₃₆ H₄₂ N₄ O₃ ×H₂ O (596.78) Calculated: C 72.46 H 7.43 N 9.39Found: 72.50 7.45 9.77 Mass spectrum: M⁺ =578

EXAMPLE 1824'-[[2-n-Propyl-4-methyl-6-[1-(2-hydroxy-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-hydroxy-ethyl)-formamide/2-hydroxy-ethylamine.

EXAMPLE 1834'-[[2-n-Propyl-4-methyl-6-[1-(3-dimethylamino-propyl)-4-isobutyl-5-methyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(3-dimethylamino-propyl)-formamide/3'-dimethylamino-propylamine.

EXAMPLE 1844'-[[2-n-Propyl-4-methyl-6-(1-carboxymethyl-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-formylglycineethylester/glycineethylester.

EXAMPLE 1854'-[[2-n-Propyl-4-methyl-6-(1-aminocarbonylmethyl-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-formylglycinamide/glycinamide.

EXAMPLE 1864'-[[2-n-propyl-4-methyl-6-[1-(2-carboxy-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4-isobutyl-5-methyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand ethyl 3-formylamino-propionate/ethyl 3-aminopropionate.

The following compounds may be obtained analogously:

4'-[[2-n-propyl-4-methyl-6-(1,5-dimethyl-4-isobutyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-(1H-tetrazol-5-yl)biphenyl

4'-[[2-n-propyl-4-methyl-6-(1-n-propyl-4-isobutyl-5-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-(1H-tetrazol-5-yl)biphenyl

4'-[[2-n-propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4-isobutyl-5-methyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-(1H-tetrazol-5-yl)biphenyl

EXAMPLE 187 Methyl4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate

A solution of 0.35 g (0.7 mMol) of methyl4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylatein 10 ml of toluene is mixed with 0.16 g palladium (10% on activatedcharcoal) under nitrogen and the mixture is refluxed for 66 hours. Thenthe toluene is evaporated off, the residue is taken up in methylenechloride, filtered and evaporated down. The crude product ischromatographed on silica gel (particle size: 0.032-0.063 mm) using aseluant methylene chloride to start with, later followed by methylenechloride/ethanol/ammonia (50:1:0.05, 20:1:0.02, 10:1:0.01 and5:1:0,005). The uniform fractions are combined and evaporated down.

Yield: 0.30 g (9% of theory), Mass spectrum: M⁺ =478

EXAMPLE 1884'-[[2-n-Propyl-4-methyl-6-(1,4,5-trimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methyl-formamide/methylamine.

Yield: 61% of theory, Melting point: 217°-219C (decomp.) C₃₁ H₃₂ N₄ O₂×0.25 H₂ O (497.13) Calculated: C 74.90 H 6.59 N 11.27 Found: 74.84 6.5811.26 Mass spectrum: M⁺ =492

EXAMPLE 1894'-[[2-n-Propyl-4-methyl-6-(1-ethyl-4,5-dimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-ethylformamide/ethylamine.

EXAMPLE 1904'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 146 from4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland N-methyl-formamide/methylamine.

EXAMPLE 1914'-[[2-n-Propyl-4-methyl-6-(1-ethyl-4,5-dimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 146 from4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland N-ethyl-formamide/ethylamine.

EXAMPLE 1924'-[[2-n-Propyl-4-methyl-6-(1-isopropyl-4,5-dimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to. Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-isopropyl-formamide/isopropylamine.

EXAMPLE 1934'-[[2-n-Propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4,5-dimethyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-dimethylaminoethyl)formamide/2-dimethylamino-ethylamine.

EXAMPLE 1944'-[[2-n-Propyl-4-methyl-6-[1-(2-morpholino-ethyl)-4,5-dimethyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-morpholinoethyl)-formamide/2-morpholino-ethylamine.

EXAMPLE 1954'-[[2-n-Propyl-4-methyl-6-[l-(2-morpholino-ethyl)-4,5-diethyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 146 from4'-[[2-n-propyl-4-methyl-6-(4,.5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland N-(2-morpholino-ethyl)-formamide/2-morpholino-ethylamine.

EXAMPLE 1964'-[[2-n-Propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4,5-dimethylimidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-methoxy-ethyl)formamide/2-methoxy-ethylamine.

EXAMPLE 1974'-[[2-n-Propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4,5-dimethylimidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 146 from4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland N-(2-methoxy-ethyl)-formamide/2-methoxy-ethylamine.

EXAMPLE 1984'-[[2-n-Propyl-4-methyl-6-[1-(2-carboxy-ethyl)-4,5-dimethylimidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-2-biphenyl-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand ethyl N-formyl-3-aminopropionate/ethyl 3-aminopropionate.

EXAMPLE 1994'-[[2-n-Propyl-4-methyl-6-(1-methyl-4,5-diethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid×0.25 H₂ O

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-methyl-formamide/methylamine.

Yield: 65% of theory, Melting point: 247°-249C (decomp.) C₃₃ H₃₆ N₄ O₂×0.25 H₂ O (525.18) Calculated: C 75.47 H 7.01 N 10.67 Found: 75.43 7.1110.68 Mass spectrum: M⁺ =520

EXAMPLE 2004'-[[2-n-Propyl-4-methyl-6-(1-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared by heating of tert.butyl 4'-[[2-n-propyl-4-methyl-6-[2-(N-methylamino)-ethylaminocarbonyl]-1H-benzimidazol-1-yl]-methyl-]-biphenyl-2-carboxylatein phosphorus oxychloride and isolating analogously to Example 151.

Yield: 30% of theory, C₂₉ H₃₀ N₄ O₂ (466.59) R_(f) value: 0.50(methylene chloride/methanol/acetic acid=2:1:0.02) Mass spectrum: (M+H)⁺=467

EXAMPLE 2014'-[[2-n-Propyl-4-methyl-6-[1-(2-dimethylamino-ethyl)-4,5-diethyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid-dihydrate-trihydrochloride

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-dimethylamino-ethyl)-formamide/2-dimethylamino-ethylamine.

Yield: 14% of theory, Melting point: from 210° C. (decomp.) C₃₆ H₄₃ N₅O₂ ×3 HCl×2 H₂ O (723.21) Calculated: C 59.79 H 6.97 N 9.69 Cl 14.71Found: 59.28 6.92 9.75 14.26 Mass spectrum: M⁺ =

EXAMPLE 2024'-[[2-n-Propyl-4-methyl-6-[1-(2-morpholino-ethyl)-4,5-diethyl-imidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-morpholino-ethyl)formamide/2-morpholino-ethylamine.

Yield: 41% of theory, Melting point: from 196° C. (decomp.) C₃₈ H₄₅ N₅O₃ (619.82) Mass spectrum: M⁺ =619

EXAMPLE 2034'-[[2-n-Propyl-4-methyl-6-[1-(2-methoxy-ethyl)-4,5-diethylimidazol-2-yl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid hydrate

Prepared analogously to Example 146 from tert.butyl4'-[[2-n-propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand N-(2-methoxy-ethyl)formamide/2-methoxy-ethylamine. C₃₅ H₄₀ N₄ O₃ ×H₂O (582.76) Calculated×H₂ O: C 72.14 H 7.27 N 9.61 Found: 71.99 7.19 9.84Mass spectrum: (M-H)⁻ =563

EXAMPLE 2044'-[[2-n-Propyl-4-methyl-6-(4,5-diethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 170 from tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-propionyl-n-propyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand phosphorusoxychloride.

Yield: 97% of theory, Melting point: 250°-255° C. C₃₂ H₃₃ N₃ O₃ (507.64)Calculated: C 75.71 H 6.55 N 8.28 Found: 75.77 6.59 8.46 Mass spectrum:M⁺ =507

EXAMPLE 2054'-[[2-n-Propyl-4-methyl-6-(4,5-diethyl-1H-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 166b from4'-[[2-n-propyl-4-methyl-6-[N-(1-propionyl-n-propyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland ammonium acetate/glacial acetic acid.

Yield: 27% of theory, Melting point: 221°-223° C. C₃₂ H₃₄ N₈ ×H₂ O(530.69) Calculated: C 70.05 H 6.61 N 20.42 Found: 70.79 6.98 18.83 Massspectrum: M⁺ =530

EXAMPLE 2064'-[[2-n-Propyl-4-methyl-6-(4,5-dimethyl-oxazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 170 from tert.butyl4'-[[2-n-propyl-4-methyl-6-[N-(1-acetyl-ethyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylateand phosphorusoxychloride.

Yield: 88% of theory, Melting point: 259°-260° C. (decomp.) C₃₀ H₂₉ N₃O₃ ×0.25 H₂ O (484.09) Calculated: C 74.44 H 6.14 N 8.68 Found: 74.336.14 8.69 Mass spectrum: M⁺ =479

EXAMPLE 2074'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2,-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl

a)4'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2'-(hydroxycarbamimidoyl)-biphenyl

To a solution of 8.4 g (0.12 Mol) of hydroxylamine-hydro-chloride in 30ml of dimethylsulfoxide are added 30 ml of a sodium methoxide solutionof 30 percent in methanol at room temperature. After 10 minutes 4.5 g (10 mMol) of4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2'-cyano-biphenylare added to this solution and the obtained suspension is heated up to9° C. for 12 hours. After cooling to room temperature the reactionmixture is poured into 200 ml of ice water. The obtained precepitate issuction filtered, washed with water, dissolved in methylene chloride andchromatographed on silica gel (particle size: 0.023-0.063 mm) using aseluant mixtures from ethyl acetate, ethanol and concentrated ammonia(19:1:0.06, 19:1:0.08, 19:1:0.1 and 9:1:0.2). The uniform fractions arecombined, evaporated, triturated with ether and dried.

Yield: 1.2 g (25% of theory), Melting point: 221°-224° C. (decomp.)

b)4'-[[2-n-Propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl

To a solution of 0.5 g (1 mMol) of4'-[[2-n-propyl-4-methyl-6-(1-methyl-5,6,7,8-tetrahydrobenzimidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2'-(hydroxycarbamimidoyl)-biphenyland 0.14 ml (1 mMol) of triethylamine in 40 ml of tetrahydrofuran areadded a solution of 0.1 ml (1 mMol) of ethyl chloroformate in 1 ml ofmethylene chloride at 5° C. After 2 hours at room temperature, theformed precipitate is suction filtered. After evaporation of thefiltrate the obtained residue is dissolved in 5 ml of xylene andrefluxed for 90 minutes. After cooling to room temperature, the reactionmixture was mixed with 20 ml of ethyl acetate, washed with water anddried over magnesium sulfate. After evaporating of the organic phase,the obtained residue is chromatographed on silica gel (particle size:0.032-0.063 mm) using as eluant methylene chloride with increasingamounts of ethanol (0 to 10%). The uniform fractions are combined,evaporated, triturated with ether and dried.

Yield: 80 mg (14% of theory), Melting point: amorphous R_(f) -value:0.33 (silica gel; ethyl acetate/methanol=3:1) Mass spectrum:

The following compound may be obtained analogeously to Example 207:

4'-[[2-n-Propyl-4-methyl-6-(1,4,5-trimethyl-imidazol-2-yl)-1H-benzimidazol-1-yl]-methyl]-2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)-biphenyl.

EXAMPLE 2084'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

a)2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazole

A mixture of 4.5 g (21 mMol) of1-methylamino-2-amino-4-fluoro-benzene-dihydrochloride and 4.3 g (21mMol) of 2-ethyl-4-methyl-benzimidazol-6-yl-carboxylic acid is stirredfor four hours at 140° C. in 100 g of polyphosphoric acid, then stirredinto about 300 g of ice water and made alkaline with concentratedammonia solution. The crude product precipitated is suction filtered,dried and then purified by column chromatography (300 g of silica gel;methylene chloride/ethanol=95:5).

Yield: 3.1 g (48% of theory), R_(f) value: 0.24 (silica gel; methylenechloride/ethanol=19:1)

b) Tert.butyl4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluorobenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate

616 mg (5.5 mMol) of potassium tert.butoxide are added to a solution of1.55 g (5 mMol) of2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazolein 30 ml of dimethylsulphoxide and the resulting mixture is stirred for15 minutes at ambient temperature. Then 1.9 g (5.5 mMol) of tert.butyl4'-bromomethyl-biphenyl-2-carboxylate are added and stirring iscontinued for a further 20 hours at ambient temperature. The mixture isthen stirred into about 80 ml of saturated sodium chloride solution, thecrude product precipitated is suction filtered and purified by columnchromatography (150 g silica gel; eluant: methylenechloride/ethanol=98:2).

Yield: 1.4 g (50% of theory), R_(f) value: 0.47 (silica gel; methylenechloride/ethanol=19:1)

c)4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

A solution of 1.4 g (2.4 mMol) of tert.butyl4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand 15 ml of trifluoroacetic acid in 30 ml of methylene chloride isstirred for 14 hours at ambient temperature, then concentrated byevaporation, the residue is mixed with about 30 ml of water and madealkaline with 2N sodium hydroxide solution. After extracting twice with30 ml of diethyl ether, the aqueous phase is acidified with 20% citricacid. The crude product precipitated is suction filtered and purified bycolumn chromatography (100 g silica gel; eluant: methylenechloride/ethanol=96:4).

Yield: 850 mg (69% of theory), Melting point: 246°-248° C. C₃₂ H₂₇ FN₄O₂ (518.60)

Calculated: C 74.11 H 5.25 N 10.80 Found: 73.95 5.34 10.80 Massspectrum: m/e=518

EXAMPLE 2094'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 208 from tert.butyl4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 87% of theory, Melting point: 269°-271° C. C₂₉ H₃₁ N₃ O₄ S(517.65) Calculated: C 67.29 H 6.04 N 8.12 Found: 67.56 6.12 8.28 R_(f)value: 0.39 (silica gel; methylene chloride/ethanol=9:1) Mass spectrum:m/e=517

EXAMPLE 2104'-[(2-Cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 208 from tert.butyl4'-[(2-cyclopropyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 50% of theory, Melting point: 245°-248° C. C₃₂ H₂₆ N₄ O₂ (498.59)Calculated: C 77.09 H 5.26 N 11.24 Found: 76.88 5.37 11.30 R_(f) value:0.63 (silica gel; methylene chloride/ethanol=9:1) Mass spectrum: m/e=498

EXAMPLE 2114'-[(2-Cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 208 from tert.butyl4'-[(2-cyclopropyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid.

Yield: 53% of theory, Melting point: 310°-312° C. C₃₂ H₃₀ N₄ O₂ (502.62)Calculated: C 76.47 H 6.02 N 11.15 Found: 76.23 5.97 10.85 R_(f) value:0.17 (silica gel; methylene chloride/ethanol=9:1) Mass spectrum: m/e=502

EXAMPLE 2124'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

a)4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl

616 mg (5.5 mMol) of potassium tert.butoxide are added to a solution of1.55 g (5 mMol) of2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazolein 30 ml of dimethylsulphoxide and the mixture is stirred for 15 minutesat ambient temperature. Then 1.5 g (5.5 mMol) of4'-bromomethyl-2-cyano-biphenyl are added and the resulting mixture isstirred for a further 20 hours at ambient temperature. Then the mixtureis stirred into approximately 80 ml of saturated sodium chloridesolution, the crude product precipitated is suction filtered andpurified by column chromatography (150 g of silica gel; eluant:methylene chloride/ethanol=97:3).

Yield: 1.9 g (76% of theory), R_(f) value: 0.43 (silica gel; methylenechloride/ethanol=19:1)

b)4'-[(2-Ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

A solution of 1.9 g (3.8 mMol) of4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl,4.1 g (76 mMol) of ammonium chloride and 4.9 g (76 mMol) of sodium azidein 30 ml of dimethylformamide is heated to 140° C. for 15 hours, then afurther 2.0 g of ammonium chloride and 2.4 g of sodium azide are addedand the mixture is heated for another 4 hours to 140° C. Then thesolution is stirred into about 80 ml of saturated sodium chloridesolution, the crude product precipitated is suction filtered andpurified by column chromatography (150 g of silica gel; eluant:methylene chloride/ethanol=19:1).

Yield: 1.25 g (61% of theory), Melting point: 267°-269° C. C₃₂ H₂₇ FN₈(542.60) Calculated: C 70.84 H 5.02 N 20.65 Found: 70.52 5.04 20.82R_(f) value: 0.60 (silica gel; methylene chloride/ethanol=9:1) Massspectrum: m/e=542

EXAMPLE 2134'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

a)4'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl

To a solution of 570 mg (1.86 mMol) of2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazole in 20 mlof dimethylsulphoxide are added 224 mg (2.0 mMol) of potassiumtert.butoxide and the mixture is stirred for 15 minutes at ambienttemperature. Then 1.11 g (2.0 mMol) of4'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are addedand the mixture is stirred for a further 3 hours at ambient temperature.Then the mixture is stirred into about 50 ml of saturated sodiumchloride solution, the crude product precipitated is suction filteredand purified by column chromatography (100 g silica gel; eluant: ethylacetate/petroleum ether=4:1).

Yield: 860 mg (59% of theory), R_(f) value: 0.56 (silica gel; ethylacetate/petroleum ether=4:1)

b)4'-[(2-Ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl]-biphenyl

A mixture of 830 mg (1.06 mMol) of4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl,2.5 ml of 1N sodium hydroxide solution and 20 ml of ethanol is stirredfor 2 hours at 80° C. The solution is then evaporated down, the residueis mixed with about 30 ml of water and made slightly acidic with glacialacetic acid. It is then extracted three times with about 20 ml ofmethylene chloride, the combined organic extracts are washed with 20 mlof water and concentrated by evaporation. The crude product thusobtained is purified by column chromatography (50 g silica gel;methylene chloride/ethanol=97:3).

Yield: 430 mg (75% of theory), Melting point: 194°-197° C. C₃₂ H₂₈ N₈ O(540.60) Calculated: C 71.10 H 5.22 N 20.73 Found: 69.99 5.36 20.54 Massspectrum: m/e=540

EXAMPLE 2144'-[(2-Ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid-hydrate

Prepared analogously to Example 208 from tert.butyl4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 72% of theory, Melting point: 207°-209° C. C₃₁ H₂₆ N₄ O₃ ×H₂ O(520.60) Calculated: C 71.52 H 5.42 N 10.76 Found: 71.22 5.37 10.76R_(f) value: 0.36 (silica gel; methylene chloride/ethanol=19:1)

EXAMPLE 214

Mixture of

4'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl

and

4'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-2-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl

A solution of 400 mg (0.74 mMol) of4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl,0.16 ml (1.1 mMol) of chloromethyl pivalate and 194 mg (1.1 mMol) ofpotassium carbonate-dihydrate in 10 ml of dimethyl formamide is stirredfor 14 hours at ambient temperature, then stirred into about 50 ml ofsaturated sodium chloride solution and extracted three times with about20 ml of methylene chloride. The combined organic extracts are washedwith water and evaporated down. The crude product thus obtained ispurified by column chromatography (50 g silica gel; eluant: methylenechloride/ethanol=98:2).

Yield: 400 mg (82% of theory), Melting point: amorphous C₃₅ H₄₁ N₇ O₄ S(655.80) Calculated: C 64.10 H 6.30 N 14.95 S 4.88 Found: 63.99 6.2214.80 5.03 R_(f) value: 0.46 (silica gel; methylenechloride/ethanol=19:1)

EXAMPLE 216

Mixture of

4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[1-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl

and

4'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[2-(pivaloyloxymethyl)-tetrazol-5-yl]-biphenyl

Prepared analogously to Example 215 from4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyland chloromethylpivalate.

Yield: 75% of theory, Melting point: 203°-205° C. C₃₈ H₄₂ N₈ O₂ (642.80)Calculated: C 71.00 H 6.59 N 17.43 Found 70.85 6.63 17.43 R_(f) value:0.43 (silica gel; methylene chloride/ethanol=19:1) Mass spectrum:m/e=642

EXAMPLE 2174'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[1-(cyclohexyloxycarbonyloxy)-ethyloxycarbonyl]-biphenyl

A solution of 504 mg (1.0 mMol) of4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid, 600 mg of 1-(cyclohexyloxycarbonyloxy)-ethyliodide and 350 mg ofpotassium carbonate in 25 ml of dimethylsulphoxide is stirred for 14hours at ambient temperature, then stirred into about 70 ml of saturatedsodium chloride solution and extracted three times with 30 ml of ethylacetate. The combined organic extracts are washed with water andevaporated down. The crude product thus obtained is purified by columnchromatography (100 g silica gel; eluant: methylenechloride/ethanol=98:2).

Yield: 325 mg (48% of theory), Melting point: 162°-164° C. C₄₁ H₄₆ N₄ O₅(674.85) Calculated: C 72.97 H 6.87 N 8.30 Found: 72.63 6.77 8.17 R_(f)value: 0.52 (silica gel; methylene chloride/ethanol=19:1) Mass spectrum:m/e=674

EXAMPLE 2184'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(pivaloyloxymethyloxycarbonyl)-biphenyl

Prepared analogously to Example 215 from4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid and chloromethylpivalate in dimethylformamide.

Yield: 76% of theory, Melting point: 142°-144° C. C₃₈ H₄₂ N₄ O₄ (618.79)Calculated: C 73.76 H 6.84 N 9.09 Found: 73.60 6.92 9.17 R_(f) value:0.40 (silica gel; methylene chloride/ethanol=19:1) Mass spectrum:m/e=618

EXAMPLE 2194'-[(2-n-Propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-2-(pivaloyloxymethyloxy-carbonyl)-biphenyl

Prepared analogously to Example 215 from4'-[(2-n-propyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid and chloromethylpivalate in dimethylformamide.

Yield: 70% of theory, Melting point: Oil C₃₅ H₄₁ N₃ O₆ S (631.80)Calculated: C 66.54 H 6.54 N 6.65 S 5.08 Found: 66.21 6.67 6.54 5.34R_(f) value: 0.49 (silica gel; methylene chloride/ethanol=19:1) Massspectrum: m/e=631

EXAMPLE 2204'-[(2-n-Propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-[1-(ethoxycarbonyloxymethyloxy)-carbonyl]-biphenyl

Prepared analogously to Example 215 from4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid and 1-(ethoxycarbonyloxy)-methylchloride in dimethylformamide.

Yield: 38.5% of theory, Melting point: 123°-125° C. C₃₇ H₄₀ N₄ O₅(620.76) Calculated: C 71.59 H 6.50 N 9.03 Found: 71.57 6.58 9.03 R_(f)value: 0.33 (silica gel; methylene chloride/ethanol=19:1) Mass spectrum:m/e=620

EXAMPLE 2214'-[(2-Ethoxy-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 213 from4'-[(2-ethoxy-4-methyl-6-(imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland sodium hydroxide solution in ethanol.

EXAMPLE 2224'-[(2-Ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(1H-tetrazol-5-yl)-biphenyl

Prepared analogously to Example 213 from4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyland sodium hydroxide solution in ethanol.

EXAMPLE 2234'-[(2-Ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 208 from tert.butyl4'-[(2-ethoxy-4-methyl-6-(5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 63% of theory, Melting point: 238°-240° C. R_(f) value: 0.62(silica gel; methylene chloride/ethanol=9:1)

EXAMPLE 2244'-[(2-Ethyl-4-methyl-6-(butanesultam-1-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 208 from tert.butyl4'-[(2-ethyl-4-methyl-6-(butanesultam-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 68% of theory, Melting point: >240° C. C₂₈ H₂₉ N₃ O₄ S (503.60)Calculated: C 66.77 H 5.80 N 8.34 Found: 66.57 5.69 8.30 R_(f) value:0.36 (silica gel; methylene chloride/ethanol=9:1)

EXAMPLE 2254'-[(2-Ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid

Prepared analogously to Example 208 from tert.butyl4'-[(2-ethyl-4-methyl-6-(3-chloro-5,6,7,8-tetrahydro-imidazo[1,2-a]-pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylateand trifluoroacetic acid in methylene chloride.

Yield: 43% of theory, Melting point: 295°-297 _C C₃₁ H₂₉ C₁ N₄ O₂(525.06) Calculated: C 70.91 H 5.57 N 10.67 Cl 6.75 Found: 70.81 5.5410.55 6.83 R_(f) value: 0.36 (silica gel; methylenechloride/ethanol=9:1)

In the Examples of Pharmaceutical Formulations which follow, anysuitable compound of formula I, particularly those compounds wherein R₄represents a carboxy- or 1H-tetrazolyl group or a group which can bemetabolised into a carboxy- or 1H-tetrazolyl group o, may be used as theactive substance:

EXAMPLE 226

Ampoules containing 50 mg of active substance per 5 ml

    ______________________________________                                        Active substance   50 mg                                                      KH.sub.2 PO.sub.4   2 mg                                                      Na.sub.2 HPO.sub.4 × 2H.sub.2 O                                                            50 mg                                                      NaCl               12 mg                                                      Water for injections ad                                                                           5 ml                                                      ______________________________________                                    

Preparation:

The buffer substances and isotonic substance are dissolved in some ofthe water. The active substance is added and, once it has beencompletely dissolved, water is added to make up the required volume.

EXAMPLE 227

Ampoules containing 100 mg of active substance per 5 ml

    ______________________________________                                        Active substance      100 mg                                                  Methyl glucamine       35 mg                                                  Glycofurol            1000 mg                                                 Polyethyleneglycol-polypropylene-                                                                   250 mg                                                  glycol block polymer                                                          Water for injections ad                                                                              5 ml                                                   ______________________________________                                    

Preparation:

Methyl glucamine is dissolved in some of the water and the activesubstance is dissolved with stirring and heating. After the addition ofsolvents, water is added to make up the desired volume.

EXAMPLE 228

Tablets containing 50 mg of active substance

    ______________________________________                                        Active substance  50.0 mg                                                     Calcium phosphate 70.0 mg                                                     Lactose           40.0 mg                                                     Corn starch       35.0 mg                                                     Polyvinylpyrrolidone                                                                             3.5 mg                                                     Magnesium stearate                                                                               1.5 mg                                                                       200.0 mg                                                    ______________________________________                                    

Preparation:

The active substance, CaHPO₄, lactose and corn starch are uniformlymoistened with an aqueous PVP solution. The mass is passed through a 2mm screen, dried at 50° C. in a circulating air dryer and screenedagain.

After the lubricant has been added, the granules are compressed in atablet making machine.

EXAMPLE 229

Coated tablets containing 50 mg of active substance

    ______________________________________                                        Active substance       50.0   mg                                              Lysine                 25.0   mg                                              Lactose                60.0   mg                                              Corn starch            34.0   g                                               Gelatin                10.0   mg                                              Magnesium stearate     1.0    mg                                                                     180.0  mg                                              ______________________________________                                    

Preparation:

The active substance is mixed with the excipients and moistened with anaqueous gelatin solution. After screening and drying the granules aremixed with magnesium stearate and compressed to form tablet cores.

The cores thus produced are covered with a coating by known methods. Acolouring may be added to the coating suspension or solution.

EXAMPLE 230

Coated tablets containing 100 mg of active substance

    ______________________________________                                        Active substance   100.0 mg                                                   Lysine             50.0 mg                                                    Lactose            86.0 mg                                                    Corn starch        50.0 mg                                                    Polyvinylpyrrolidone                                                                              2.8 mg                                                    Microcrystalline cellulose                                                                       60.0 mg                                                    Magnesium stearate  1.2 mg                                                                       350.0 mg                                                   ______________________________________                                    

Preparation:

The active substance is mixed with the excipients and moistened with anaqueous PVP solution. The moist mass is passed through a 1.5 mm screenand dried at 45° C. After drying, it is screened again and the magnesiumstearate is added. This mixture is compressed into cores.

The cores thus produced are covered with a coating by known methods.Colourings may be added to the coating suspension or solution.

EXAMPLE 231

Capsules containing 250 mg of active substance

    ______________________________________                                        Active substance 250.0 mg                                                     Corn starch       68.5 mg                                                     Magnesium stearate                                                                              1.5 mg                                                                       320.0 mg                                                     ______________________________________                                    

Preparation:

The active substance and corn starch are mixed together and moistenedwith water. The moist mass is screened and dried. The dry granules arescreened and mixed with magnesium stearate. The final mixture is packedinto size 1 hard gelatine capsules.

EXAMPLE 232

Oral suspension containing 50 mg of active substance per 5 ml

    ______________________________________                                        Active substance  50.0 mg                                                     Hydroxyethylcellulose                                                                           50.0 mg                                                     Sorbic acid        5.0 mg                                                     70% sorbitol      600.0 mg                                                    Glycerol          200.0 mg                                                    Flavouring        15.0 mg                                                     Water ad           5.0 ml                                                     ______________________________________                                    

Preparation:

Distilled water is heated to 70° C. Hydroxyethyl-cellulose is dissolvedtherein with stirring. With the addition of sorbitol solution andglycerol the mixture is cooled to ambient temperature. At ambienttemperature, sorbic acid, flavouring and active substance are added. Thesuspension is evacuated with stirring to remove any air. One dose of 50mg is contained in 5.0 ml.

EXAMPLE 233

Suppositories containing 100 mg of active substance

    ______________________________________                                        Active substance                                                                               100.0 mg                                                     Solid fat       1600.0 mg                                                                     1700.0 mg                                                     ______________________________________                                    

Preparation:

The hard fat is melted. At 40° C. the ground active substance ishomogeneously dispersed in the melt. It is cooled to 38° C. and pouredinto slightly chilled suppository moulds.

What is claimed is:
 1. A compound of the formula I ##STR30## wherein R₁is in the 4-position and represents a C₁₋₄ -alkyl, C₃₋₇ -cycloalkyl ortrifluoromethyl group,R₂ represents an imidazol-4-yl group substitutedin the 1-position by a C₂₋₄ -alkyl group which is, in turn, substitutedin 2-, 3- or 4-position by a morpholino group, or R₂ represents animidazol-4-yl group substituted in the 1-position by a C₂₋₄ -alkyl groupwhich is, in turn, substituted in 2-, 3- or 4-position by a morpholinogroup, and which imidazo group is further substituted in the 2-positionby a C₁₋₆ -alkyl group or by a phenyl group, R₃ represents a C₁₋₅ -alkylgroup or cyclopropyl, and R₄ denotes a 1H-tetrazolyl group or an R_(a)O--CO-- group, whereinR_(a) denotes a hydrogen atom or astraight-chained or branched C₁₋₄ -alkyl group,or a pharmaceuticallyacceptable salt thereof.
 2. A compound of formula I, in accordance withclaim 1, wherein R₂ is in the 6-position, or a pharmaceuticallyacceptable salt thereof.
 3. A compound of fornmla I, in accordance withclaim 2, wherein R₄ is a 1H-tetrazolyl or carboxy group, or apharmaceutically acceptable salt thereof.
 4. A compound of formula I, inaccordance with claim 3, wherein R₂ is an imidazol-4-yl groupsubstituted in the 1-position by a C₂₋₄ -alkyl group which is, in turn,substituted in 2-, 3- or 4-position by a morpholino group, or apharmaceutically acceptable salt thereof.
 5. A compound of formula I, inaccordance with claim 4, wherein R₂ is an imidazol-4-yl groupsubstituted in the 1-position by a 2-morpholinoethyl group, or apharmaceutically acceptable salt thereof. 6.4'-[(2-n-Propyl-4-methyl-6-(1-(2-N-morpholinoethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylicacid or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a compound as in any one of claims 1, 2, 3, 4, 5or
 6. 8. A method for treating hypertension which comprisesadministering to a mammalian host suffering from the same anantihypertensive amount of a compound as in any one of claims 1, 2, 3,4, 5 or 6.